Hospital For Special Surgery Fund Inc

STEROID THERAPY AND CYTOKINES IN RHEUMATIC DISEASES

INHIBITION OF STAT3 AND INFLAMMATORY CYTOKINE PRODUCTION

PREDICTORS OF PREGNANCY OUTCOME IN SLE AND APS

VASCULAR QUIESCENCE AND STABILIZATION IN IMMUNITY

FC RECEPTORS & CYTOKINE BALANCE IN RHEUMATOID ARTHRITIS

CYTOKINE REGULATION OF RA SYNOVIOCYTE PHENOTYPE

NEGATIVE REGULATION OF HUMAN OSTEOCLASTOGENESIS

FT-IR MICROSCOPY OF MINERAL STRUCTURE IN OSTEOPOROSIS

GLUCOCORTICOID-REGULATED TRANSCRIPTION NETWORKS IN MACROPHAGE BIOLOGY

MAGNETIC RESONANCE IMAGING AS A BIOMARKER FOR ADVERSE LOCAL TISSUE REACTION IN IN

ADAMS: KEY REGULATORS OF EGFR SIGNALING

DEFINING COMMON MOLECULAR PARAMETERS FOR ONSET AND PROGRESSION OF OSTEOARTHRITIS

REGULATION OF OSTEOCLASTOGENESIS AND ARTHRITIC BONE RESORPTION BY RBP-J

REGULATION OF ADULT TENDON GROWTH AND REGENERATION BY SCLERAXIS

FUNCTIONAL CONSEQUENCES OF INTERGENIC AUTOIMMUNE DISEASE RISK VARIANTS - ABSTRACT SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A MULTISYSTEM AUTOIMMUNE DISEASE CHARACTERIZED BY HIGH MORBIDITY AND MORTALITY, AND LARGELY INEFFECTIVE TREATMENTS. SLE IS GENETICALLY COMPLEX WITH STRONG FAMILIAL AGGREGATION AND HIGH HERITABILITY. MOST OF THE RISK ALLELES FOR SLE ARE NOT PROTEIN-CODING SEQUENCE CHANGES, SUGGESTING THAT A SIGNIFICANT PORTION OF DISEASE RISK IS MEDIATED BY REGULATORY VARIANTS IN THE NONCODING GENOME. AT A RECENTLY IDENTIFIED INTERGENIC SLE RISK LOCUS ON CHROMOSOME 12Q12, OUR IN SILICO ANALYSES IMPLICATE THE RISK VARIANTS AS EQTLS THAT IMPACT TRANSCRIPTION OF GENES IN MULTIPLE BIOLOGICAL PATHWAYS THAT CONTRIBUTE TO SLE IMMUNOPATHOLOGY, INCLUDING TYPE I INTERFERON (IFN) AND ANTI-VIRAL GENES. THIS INTERGENIC SLE RISK LOCUS IS ENRICHED IN REGULATORY ELEMENTS AND RESIDES ADJACENT TO SEVERAL LONG NON-CODING RNA (LNCRNA) GENES. IN THIS PROPOSAL, WE OUTLINE A COMPREHENSIVE SET OF MECHANISTIC AND FUNCTIONAL EXPERIMENTS TO UNDERSTAND THE ROLE OF THE 12Q12 RISK LOCUS IN HUMAN IMMUNE CELLS. WE HYPOTHESIZE THAT SEVERAL VARIANTS WITHIN CIS-REGULATORY ELEMENTS AT THE 12Q12 LOCUS ALTER THE EXPRESSION OF ADJACENT LNCRNAS, WHICH IN TURN EXERT CIS AND TRANS EFFECTS ON IMMUNE SYSTEM GENES RESULTING IN INCREASED SLE RISK. AN ALTERNATE HYPOTHESIS IS THAT THE 12Q12 LOCUS COULD BE A LONG-RANGE ENHANCER FOR NEARBY PROTEIN- CODING AND/OR NON-CODING GENES. THESE HYPOTHESES ARE NOT MUTUALLY EXCLUSIVE, AND OUR EXPERIMENTAL DESIGN WILL DETECT EACH POSSIBILITY. IN AIM 1, WE WILL DETERMINE THE OVERALL IMPACT OF THE INTERGENIC 12Q12 LOCUS ON GENE REGULATION IN PRIMARY IMMUNE CELLS AND SELECTED CELL LINES. INTEGRATIVE ANALYSES WILL BE USED TO INFER LNCRNA INFLUENCES ON MRNA NETWORKS. CANDIDATE LNCRNAS FROM THESE ANALYSES WILL BE KNOCKED DOWN WITH SIRNAS TO CONFIRM THEIR FUNCTION. IN AIM 2, WE WILL IDENTIFY CAUSAL CIS-REGULATORY ELEMENTS IN THE INTERGENIC 12Q12 REGION. WE WILL USE COMPLEMENTARY METHODS TO IDENTIFY LIKELY REGULATORY ELEMENTS, AND PUTATIVE CAUSAL ELEMENTS WILL BE KNOCKED OUT IN CELL LINES TO CONFIRM FUNCTION AND REVERSION TO A NON-RISK CELLULAR PHENOTYPE. WE EXPECT TO FIND THAT THE INTERGENIC 12Q12 LOCUS INFLUENCES THE EXPRESSION OF ADJACENT LNCRNAS AND/OR NEIGHBORING PROTEIN-CODING OR NON-CODING GENES IN A CELL TYPE-SPECIFIC MANNER, RESULTING IN SIMULTANEOUS MODULATION OF MULTIPLE BIOLOGICAL PATHWAYS INVOLVED IN SLE PATHOGENESIS. THIS KNOWLEDGE COULD SUGGEST NOVEL THERAPEUTIC TARGETS FOR SLE THAT WOULD INFLUENCE MULTIPLE PATHOGENIC PATHWAYS. THIS REPRESENTS A NOVEL MECHANISM OF DISEASE IN SLE AND PROVIDES AN ILLUSTRATION OF HOW INTERGENIC RISK VARIANTS CAN FUNCTION IN COMPLEX DISEASE PATHOGENESIS.

ROLE OF DEVELOPMENTAL SIGNALING PATHWAYS IN MAINTENANCE OF SPINAL DISCS - PROJECT SUMMARY/ ABSTRACT AGING IS A SIGNIFICANT RISK FACTOR FOR THE ONSET OF SEVERAL DEGENERATIVE DISEASES, INCLUDING SPINAL OR INTERVERTEBRAL DISC (IVD) DEGENERATION AND ASSOCIATED CHRONIC BACK PAIN. IVD DEGENERATION AND CHRONIC BACK PAIN ARE TOP NEUROLOGICAL DISORDERS AND SUBSTANTIAL FINANCIAL BURDEN, BUT WITH NO THERAPY OR CURE. EACH IVD HAS A CENTRAL CORE OF NUCLEUS PULPOSUS (NP), SURROUNDED BY ORTHOGONAL LAYERS OF ANNULUS FIBROSUS (AF), TOGETHER SANDWICHED BETWEEN A PAIR OF ENDPLATES THAT CONNECT THE IVD TO THE VERTEBRAL BODIES. MUCH REMAINS TO BE LEARNED ABOUT THE CRITICAL REGULATORS OF IVD GROWTH, MATURATION, AND MAINTENANCE, AND WHETHER THEIR LOSS WITH AGE RESULTS IN IVD PATHOLOGIES. WE WILL USE CONDITIONAL GENETIC MOUSE MODELS, LINEAGE TRACING, HETEROCHRONIC IVD ORGAN CULTURE, ANALYSIS OF HUMAN DISC SAMPLES, AND UNBIASED APPROACHES OF HIGH THROUGHPUT TRANSCRIPTOMICS TO IDENTIFY CRUCIAL DEVELOPMENTAL REGULATORS', INCLUDING SONIC HEDGEHOG (SHH), IN IVD MAINTENANCE TO FILL IN THESE GAPS. OUR CENTRAL HYPOTHESIS IS THAT SHH-EXPRESSION BY THE NP CELLS IS ESSENTIAL FOR GROWTH AND MATURATION OF THE IVD, AND ITS AGE-RELATED LOSS LEADS TO THE IVD PATHOLOGIES. THE EXPRESSION OF SHH SIGNALING LIGAND BY THE NOTOCHORD IS CRUCIAL FOR EMBRYOGENESIS. PREVIOUSLY, WE SHOWED THAT POSTNATAL NP CELLS CONTINUE TO EXPRESS SHH, AND SHH SIGNALING REGULATES NP CELL PROLIFERATION AND ECM PRODUCTION BY NP AND AF. THOUGH ALL NP CELLS ARE DESCENDANTS OF SHH-EXPRESSING NOTOCHORD CELLS, OUR PRELIMINARY DATA REVEALS THAT MOST OF THEM TURN-OFF SHH EXPRESSION AFTER BIRTH. BESIDES, AGE-RELATED DECLINE IN SHH EXPRESSION IS ASSOCIATED WITH TERMINAL DIFFERENTIATION OF NP CELLS INTO MULTINUCLEATED SYNCYTIUM AND SUBSEQUENT LOSS ALONG WITH THE DECLINED EXPRESSION OF ECM PROTEINS THAT ARE IMPORTANT FOR IVD FUNCTION. OUR PRELIMINARY DATA ALSO SHOW THAT CONDITIONAL TARGETING OF SHH IN ADULT MICE ACCELERATES IVD AGING, ALONG WITH THE LOSS OF NP CELLS, PROVIDING THE LOGICAL PREMISE FOR THIS NEW PROJECT. THESE DATA INDICATE THAT SHH SIGNALING IS CRUCIAL; HOWEVER, WE DO NOT KNOW ITS PRECISE FUNCTION DURING GROWTH AND MATURATION AND WHETHER IT IS CRITICAL FOR AGING IVDS. AIM 1 WILL TEST THE HYPOTHESIS THAT SHH IS A CRITICAL SIGNALING PATHWAY AND ITS DOWNSTREAM REGULATORS PLAY A DISTINCT ROLE DURING INFANCY AND MATURATION, AND ITS LOSS CAUSES IVD PATHOLOGIES. AIM 2 WILL TEST THE HYPOTHESIS THAT SHH-EXPRESSING NP CELLS ARE THE PROGENITOR CELLS, AND THE STOCHASTIC EXPRESSION OF SHH REGULATES ALL NP CELLS' MOLECULAR HETEROGENEITY. AIM 3 WILL INVESTIGATE THE BENEFICIAL EFFECTS OF SHH SIGNALING FOR DELAYING AGING. WE EXPECT THAT THE COMPLETION OF THIS STUDY WILL PROVIDE INSIGHTS INTO THE ROLE OF SHH AS A CRITICAL REGULATOR OF GROWTH AND MATURATION OF THE IVD AND IDENTIFY AVENUES FOR TARGETING SUCH MOLECULES TO REVERSE OR DELAY THE AGING PROCESS AND IMPROVE THE QUALITY OF LIFE OF THE AGING POPULATION.

ROLE OF SHH/BRACHYURY AXIS IN THE MAINTENANCE OF THE POSTNATAL INTERVERTEBRAL DISC - PROJECT SUMMARY/ ABSTRACT THE GOAL OF THIS PROPOSAL IS TO IDENTIFY THE ROLE OF CRITICAL DEVELOPMENTAL MOLECULES IN GROWTH AND MAINTENANCE OF THE POSTNATAL INTERVERTEBRAL DISC (IVD, OR DISC), AND HOW THE LOSS OF THESE MOLECULES WITH AGE RESULTS IN PATHOLOGICAL CHANGES IN THE DISC. THE DISC IS A CARTILAGINOUS STRUCTURE PRESENT BETWEEN EACH VERTEBRA. THE DISC HAS THREE COMPONENTS: NOTOCHORD DERIVED CENTRAL NUCLEUS PULPOSUS (NP), SURROUNDED BY ORTHOGONAL LAYERS OF ANNULUS FIBROSUS (AF), AND ENDPLATE (EP) ADJACENT TO THE GROWTH PLATE. WITH AGE OR INJURY, THE DISC UNDERGOES DEGENERATIVE CHANGES LEADING TO CHRONIC LOWER BACK PAIN (CLBP) AFFECTING ALMOST 80% OF THE ADULT US POPULATION. MUCH REMAINS TO BE LEARNED ABOUT THE CELLULAR AND MOLECULAR BASIS OF DISC GROWTH DIFFERENTIATION, AND AGING, THAT HAS LIMITED DEVELOPMENT OF EFFECTIVE THERAPIES. WE WILL USE CONDITIONAL GENETIC MOUSE MODELS, LINEAGE-TRACING, AND DISC INJURY MODELS TO IDENTIFY THE FUNCTION(S) OF A CRUCIAL DEVELOPMENTAL REGULATOR BRACHYURY (BRA) IN THE DISC. OUR CENTRAL HYPOTHESIS IS THAT BRA-EXPRESSION BY THE NP CELLS IS ESSENTIAL FOR DISC GROWTH AND MAINTENANCE, AND ITS LOSS DURING AGING LEADS TO THE PATHOLOGICAL CHANGES IN THE DISC. BRA IS A T-BOX TRANSCRIPTION FACTOR AND A NOTOCHORDAL MARKER. PREVIOUSLY, WE SHOWED THAT POSTNATAL NP CELLS EXPRESS BRA; BUT IT’S EXPRESSION DECREASES WITH AGE. WE ALSO FOUND THAT SONIC HEDGEHOG (SHH), AN IMPORTANT NOTOCHORD SIGNAL SECRETED BY NP CELLS, REGULATES POSTNATAL DISC GROWTH AND DIFFERENTIATION, AND REGULATES BRA EXPRESSION. WHILE THE TOTAL NUMBER OF NP CELLS DECREASED WITH AGE, THE BRA-EXPRESSING NP CELLS ALSO DECREASED WITH AGE AND WERE REPLACED BY NON-BRA-EXPRESSING "CHONDROCYTE-LIKE CELLS" (CLCS). THE LINEAGE RELATIONSHIP BETWEEN CLCS AND THE BRA-EXPRESSING CELLS THEY REPLACE IS UNKNOWN, NOR IS IT KNOWN HOW (OR IF) THE LOSS OF BRA EXPRESSION LEADS TO DISC AGING. OUR PRELIMINARY DATA SHOWED THAT ALL NP CELLS ARE LOST IN AN AGED MOUSE DISC. WE ALSO SHOWED THAT CONDITIONAL TARGETING OF SHH IN ADULT MOUSE ACCELERATES DISC AGING, ALONG WITH THE LOSS OF BRA EXPRESSION. WE FURTHER SHOWED THAT HAPLOINSUFFICIENCY OF BRA ACCELERATES DISC AGING, PROVIDING THE LOGICAL PREMISE FOR THIS NEW PROJECT. AIM 1 TESTS THE HYPOTHESIS THAT BRA IS A PRIMARY TRANSCRIPTIONAL REGULATOR DOWNSTREAM OF SHH SIGNALING, AND REGULATES GROWTH AND MAINTENANCE OF POSTNATAL DISC. AIM 2 WILL TEST THE HYPOTHESIS THAT NP CELLS DIVERGE INTO TWO MOLECULARLY HETEROGENEOUS POPULATIONS, WHICH DIFFER WITH RESPECT TO SHH AND BRA EXPRESSION. AIM 3 WILL TEST THE HYPOTHESIS THAT BRA CONTROLS THE SURVIVAL OF NP CELLS, AND PREVENTS THEM FROM DIFFERENTIATING INTO "CHONDROCYTE-LIKE" CELLS. WE EXPECT THAT THE FINDINGS FROM THIS STUDY WILL PROVIDE INSIGHTS INTO THE ROLE OF DEVELOPMENTAL MOLECULES IN THE MAINTENANCE OF POSTNATAL DISC DURING GROWTH AND AGING, AND WILL IDENTIFY AVENUES FOR TARGETING SUCH MOLECULES TO REVERSE THE AGING PROCESS, AIDING THE DEVELOPMENT OF THERAPEUTICS FOR THE TREATMENT OF DISC RELATED DISORDERS AND LBP.

POST-INITIATION CONTROL OF TRANSCRIPTION IN INFLAMMATORY MACROPHAGES

PTH (1-34) AND PELVIC FRACTURE HEALING: A RANDOMIZED CONTROLLED TRIAL

HOSPITAL FOR SPECIAL SURGERY RESEARCH INSTITUTE RHEUMATOLOGY TRAINING

MECHANISMS CONTROLLING ABC DIFFERENTIATION AND FUNCTION IN SLE - ABSTRACT ABNORMALITIES IN B CELL SUBSETS PLAY A KEY ROLE IN SLE, A DISEASE THAT, IN ADDITION TO AUTOAB PRODUCTION AND MULTI-ORGAN INVOLVEMENT, OFTEN INCLUDES UPREGULATION OF INTERFERON STIMULATED GENES (ISGS). ONE OF THE HALLMARKS OF SLE IS THAT IT PREFERENTIALLY AFFECTS WOMEN. BOTH SEX HORMONES AND THE X CHROMOSOME (WHERE TLR7 IS LOCATED) HAVE BEEN IMPLICATED IN THE HEIGHTENED SUSCEPTIBILITY OF WOMEN TO SLE AND TO OTHER AUTOIMMUNE DISORDERS. UNDERSTANDING THE MOLECULAR MECHANISMS THAT UNDERLIE THE SEX-BIAS THAT ACCOMPANIES SLE PATHOGENESIS WILL THUS PROVIDE CRITICAL INFORMATION INTO THE DEVELOPMENT OF AUTOIMMUNITY AND HELP UNCOVER NOVEL THERAPEUTIC TARGETS. WHILE EXPANSION OF GERMINAL CENTER (GC) B CELLS AND PLASMABLASTS/PLASMA CELLS (PB/PC) HAS LONG BEEN ASSOCIATED WITH SLE, RECENT STUDIES HAVE IMPLICATED A NOVEL B CELL SUBSET, TERMED AGE/AUTOIMMUNE-ASSOCIATED B CELLS (ABCS), IN LUPUS PATHOGENESIS. IN ADDITION TO CLASSICAL B CELL MARKERS, ABCS ALSO EXPRESS CD11C AND THE TRANSCRIPTION FACTOR T-BET. FORMATION OF ABCS IS PROMOTED BY A COMBINATION OF SIGNALS THAT INCLUDES TLR7 OR TLR9 ENGAGEMENT AND CYTOKINES LIKE IFN-G AND IL-21. ABERRANT ACCUMULATION OF ABCS IS OBSERVED BOTH IN MURINE LUPUS AND IN SLE PATIENTS WHERE THEY ARE MAJOR PRODUCERS OF AUTOABS AND CORRELATE WITH DISEASE ACTIVITY AND CLINICAL MANIFESTATIONS. OUR LAB HAS HAD A LONG-STANDING INTEREST IN DISSECTING THE REGULATION AND FUNCTION OF IRF FAMILY MEMBERS, WHICH HAVE EMERGED AS KEY CONTROLLERS OF B CELL RESPONSES. WHILE IDENTIFYING IRF-INTERACTING PROTEINS, WE ISOLATED A PROTEIN TERMED DEF6. DEF6 AND ITS ONLY OTHER HOMOLOGUE, SWAP-70, PLAY AN IMPORTANT IMMUNOREGULATORY ROLE IN HUMANS AND MICE. DEF6 IS A GENETIC RISK FACTOR FOR HUMAN SLE AND BIALLELIC MUTATIONS IN DEF6 RESULT IN EARLY-ONSET SYSTEMIC AUTOIMMUNITY. FURTHERMORE, IN C57BL/6 MICE, THE CONCOMITANT LACK OF DEF6 AND SWAP-70 (DOUBLE-KNOCKOUT MICE=DKOS) LEADS TO THE SPONTANEOUS DEVELOPMENT OF SLE, WHICH, SIMILARLY TO HUMANS, PREFERENTIALLY AFFECTS FEMALE MICE. LUPUS DEVELOPMENT IN DKO MICE IS ACCOMPANIED BY A MARKED ACCUMULATION OF ABCS, WHICH IS CONTROLLED BY IRF5. WE HAVE RECENTLY FOUND THAT, AS COMPARED TO ABCS FROM DKO MALES, ABCS FROM DKO FEMALES EXPAND TO A GREATER EXTENT, EXPRESS AN ISG SIGNATURE, AND READILY PRODUCE AUTOABS UPON TLR7 STIMULATION. FURTHERMORE, IN COMPARISON WITH DKO MALES, DKO FEMALES ACCUMULATE GREATER NUMBERS OF GC B CELLS AND PB/PCS THAT CONTAIN CD11C+ SUBSETS. DYSREGULATING TLR7 EXPRESSION IN DKO MALES RESULTS IN A MARKED EXPANSION OF ABCS AND OTHER B CELL EFFECTOR LINEAGES INCLUDING CD11C-EXPRESSING B CELL SUBSETS AND PROMOTES AUTOAB PRODUCTION AND DISEASE DEVELOPMENT IN DKO MALES. TAKEN TOGETHER THESE DATA SUGGEST THAT SEXUAL DIMORPHISM UNDERLIES SEVERAL ASPECTS OF ABC BIOLOGY IN AUTOIMMUNE SETTINGS. IN THIS PROPOSAL WE WILL INVESTIGATE THE HYPOTHESIS THAT SEX- SPECIFIC MECHANISMS CONTROL THE FUNCTION AND DIFFERENTIATION OF ABCS AS WELL AS CHARACTERIZE THE DEVELOPMENTAL RELATIONSHIPS BETWEEN ABCS AND OTHER EFFECTOR B CELL LINEAGES.

REGULATION OF BONE HOMEOSTASIS AND REMODELING BY LONG NONCODING RNA MALAT1 - REGULATION OF BONE HOMEOSTASIS AND REMODELING BY LONG NONCODING RNA MALAT1 BONE HOMEOSTASIS IS MAINTAINED BY CONSTANT AND DYNAMIC REMODELING BETWEEN OSTEOCLAST-MEDIATED BONE RESORPTION AND OSTEOBLAST/OSTEOCYTE-MEDIATED BONE FORMATION. THE BALANCE OF BONE REMODELING PROCESS, HOWEVER, IS OFTEN DISRUPTED IN PATHOLOGICAL CONDITIONS, SUCH AS IN OSTEOPOROSIS AND RHEUMATOID ARTHRITIS. THE MECHANISMS THAT REGULATE BONE REMODELING ARE NOT FULLY UNDERSTOOD. RECENT GENOMIC STUDIES HAVE UNVEILED FUNCTIONAL LONG NONCODING RNAS (LNCRNAS), AND TARGETING LNCRNAS PROVIDED EXCITING NEW DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES FOR HUMAN DISEASES. THE LNCRNAS INVOLVED IN BONE REMODELING, HOWEVER, ARE UNDERAPPRECIATED. MALAT1 IS ONE OF THE MOST CONSERVED AND ABUNDANT NUCLEAR LNCRNAS. THE FUNCTION OF MALAT1 IS UNKNOWN IN BONE HOMEOSTASIS AND REMODELING. WE REVEALED, FOR THE FIRST TIME, THAT MALAT1 KO MICE EXHIBIT SIGNIFICANT OSTEOPOROTIC BONE PHENOTYPE CHARACTERIZED WITH ENHANCED OSTEOCLASTIC BONE RESORPTION, BUT REDUCED OSTEOBLASTIC BONE FORMATION IN VIVO. THUS, MALAT1 DELETION UNCOUPLED THE NORMAL BONE REMODELING BETWEEN OSTEOBLASTS AND OSTEOCLASTS. MALAT1 ACTS CELL-AUTONOMOUSLY IN OSTEOBLASTS TO PROMOTE OSTEOBLAST DIFFERENTIATION, BUT SUPPRESSES OSTEOCLASTOGENESIS IN A NON-AUTONOMOUS MANNER IN VIVO. MOREOVER, MALAT1 MODULATES CROSSTALK BETWEEN OSTEOBLASTS AND OSTEOCLASTS. MECHANISTICALLY, MALAT1 DEFICIENCY SIGNIFICANTLY REDUCED NUCLEAR LOCALIZATION OF SS-CATENIN DURING OSTEOBLASTOGENESIS. THE GENES ENRICHED IN PATHWAYS OF OSTEOBLAST SIGNALING, OSSIFICATION, AND WNT/SS- CATENIN PATHWAY WERE SELECTIVELY AND SIGNIFICANTLY SUPPRESSED IN MALAT1 KO OSTEOBLASTS. THESE FINDINGS IDENTIFY LNCRNA MALAT1 AS A NOVEL BONE REMODELING REGULATOR THAT IMPACTS SKELETAL HOMEOSTASIS BY CONTROLLING BOTH BONE FORMATION AND RESORPTION. IN THIS APPLICATION, WE WILL APPLY ROBUST GENETIC APPROACHES TO INVESTIGATE THE FUNCTIONAL IMPORTANCE OF MALAT1 IN OSTEOBLAST LINEAGE AND THE MECHANISMS BY WHICH MALAT1 REGULATES OSTEOGENESIS AND OSTEOBLAST-OSTEOCLAST CROSSTALK. SPECIFICALLY, WE WILL 1) DISSECT AND DEFINE THE FUNCTION OF MALAT1 IN OSTEOBLAST LINEAGE AT VARIOUS STAGES OF DIFFERENTIATION IN VIVO USING GENETIC APPROACHES; 2) INVESTIGATE THE MECHANISMS BY WHICH MALAT1 REGULATES OSTEOGENESIS AND OSTEOBLAST-OSTEOCLAST CROSSTALK. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL INTRODUCE FUNCTIONAL LNCRNAS INTO BONE FIELD, YIELD NOVEL INSIGHTS INTO LNCRNA-MEDIATED MECHANISMS THAT REGULATE BONE HOMEOSTASIS AND REMODELING, AND WILL PROVIDE A RATIONAL FRAMEWORK FOR DEVELOPING LNCRNA-BASED NEW OR ALTERNATIVE THERAPEUTIC APPROACHES FOR SKELETAL DISEASES.

MACROPHAGES IN HUMAN AUTOIMMUNE TISSUE PATHOLOGY

ROLE OF PLASMACYTOID DENDRITIC CELLS IN AUTOIMMUNITY

RHO GTPASE-MEDIATED PATHWAYS IN AUTOIMMUNE ARTHRITIS

DIVERSITY SUPPLEMENT: HOW PARTIAL MENISCECTOMY AFFECTS CONTACT MECHANICS AND TISSUE RESPONSE

MUSCULOSKELETAL REPAIR AND REGENERATION

DIV. SUPP.: MECHANOBIOLOGICAL RISK FACTORS FOR INITIATED POST TRAUMATIC OSTEOARTHRITIS

MOLECULAR PATHWAYS IN TREATMENT RESPONSE AND FLARE IN RA

ROLE OF IRHOMS AND ADAM17 IN EGFR AND TNFALPHA SIGNALING

REGULATORY MECHANISMS CONTROLLING TFH RESPONSES IN LUPUS

THE CROSSTALK BETWEEN MYC AND METABOLISM DURING OSTEOCLASTOGENESIS

NOVEL SIGNALING PATHWAYS IN LUPUS PATHOGENESIS

A WNT/SHH SIGNALING LOOP CONTROLS INTERVERTEBRAL DISC GROWTH AND DIFFERENTIATION

A NOVEL REGULATING PATHWAY IN OSTEOCLASTOGENESIS AND ARTHRITIC BONE RESORPTION

MECHANISMS OF INFLAMMATORY BONE REMODELING

MODULATION OF FIBRONECTIN TO IMPROVE INTEGRATION OF DENTAL IMPLANT MATERIALS

MECHANISMS OF IMMUNOSUPPRESSIVE ACTIONS OF GLUCOCORTICOIDS

EFFECTIVE TREATMENT OF FEMORAACETABULAR IMPINGEMENT OF THE HIP

SELECTIVE REGULATION OF MACROPHAGE ACTIVATION

ORIGINS AND FUNCTIONS OF INTRAMUSCULAR MACROPHAGES IN DUCHENNE MUSCULAR DYSTROPHY

ESE 1 A NOVEL TRANSCRIPTIONAL REGULATOR OF CARTILAGE REMODELING

COMBINED ENGINEERING AND ORTHOPAEDICS TRAINING PROGRAM - THE GOALS OF THE HOSPITAL FOR SPECIAL SURGERY (HSS) COMBINED ENGINEERING AND ORTHOPAEDICS TRAINING PROGRAM ARE TO IDENTIFY, TRAIN, AND EMPOWER A SELECT GROUP OF HIGH POTENTIAL INVESTIGATORS TO UTILIZE THE PRINCIPLES OF ENGINEERING TO ADVANCE PATIENT CARE THROUGH INTERDISCIPLINARY RESEARCH WHILE NURTURING THEM TO BECOME SUCCESSFUL ACADEMIC AND CLINICAL LEADERS IN THE MUSCULOSKELETAL AND ORTHOPAEDIC SCIENCES. THESE GOALS WILL BE ACHIEVED BY: (I) CAREFULLY SELECTING EXCEPTIONAL AND HIGHLY MOTIVATED PRE-DOCTORAL AND POST- DOCTORAL TRAINEES, (II) PROVIDING THEM WITH UNIQUE TRAINING, MENTORING, AND RESEARCH OPPORTUNITIES ADAPTED TO A SUB-SPECIALTY ACADEMIC HOSPITAL, AND (II) PLACING AN EMPHASIS ON INTERDISCIPLINARY APPROACHES AND FOCUSED MENTORING TO ADDRESS CLINICALLY RELEVANT RESEARCH PROBLEMS. APPLICATIONS TO FILL TWO PRE-DOCTORAL POSITIONS WILL BE INVITED FROM DIVERSE GRADUATE STUDENTS IN THE SCHOOL OF ENGINEERING AT CORNELL UNIVERSITY. TRAINEE SELECTION IS BASED ON OUTSTANDING PERFORMANCE IN AN EXISTING MANDATORY SUMMER ‘IMMERSION’ TERM AT HSS, A STRONG SUPPORTING LETTER BY AN HSS-BASED CLINICAL COLLABORATOR, AND A COMMITMENT TO SPEND A MINIMUM OF ONE FULL SEMESTER AT HSS. APPLICATIONS FOR TWO POST-DOCTORAL POSITIONS WILL BE INVITED FROM: (I) HIGH CALIBER AND DIVERSE RESIDENTS IDENTIFIED BY HSS CLINICAL SERVICE CHIEFS AND THE TRAINING PROGRAM EXECUTIVE STEERING COMMITTEE AS RISING-STARS CAPABLE OF PURSUING CLINICIAN-SCIENTIST CAREER PATHWAYS, AND (II) PHD POST-DOCTORAL FELLOWS WHO HAVE DEMONSTRATED EXEMPLARY POTENTIAL THROUGH PRIOR GRANT SUPPORT, HIGHLY CITED PEER-REVIEWED PUBLICATIONS, AND STRONG CROSS-DISCIPLINARY COLLABORATIONS. ADDITIONAL KEY SELECTION CRITERIA FOR ALL POSITIONS ARE STRONG RESEARCH PLANS THAT MEET THE MISSION OF THE TRAINING PROGRAM, A DESIRE TO PURSUE AN ACADEMIC CAREER, AND A STRONG PRECEPTOR. A KEY STRENGTH TO THE TRAINING PROGRAM IS THE CENTRAL AND UNIFYING 40+ YEAR RELATIONSHIP BETWEEN HSS AND THE SCHOOL OF ENGINEERING AT CORNELL UNIVERSITY. THIS RELATIONSHIP HAS BEEN RECENTLY REORGANIZED INTO A REVITALIZED CROSS-INSTITUTIONAL CENTER: CAMEO (CENTER FOR ADVANCED MATERIALS AND ENGINEERING IN ORTHOPAEDICS) FROM WHICH TRAINING PROGRAM PRECEPTORS ARE DRAWN. PRECEPTORS INCLUDE SCIENTISTS AND CLINICIAN- SCIENTISTS WITH STRONG TRACK RECORDS OF CONDUCTING FEDERALLY-FUNDED RESEARCH APPLYING ENGINEERING PRINCIPLES AIMED AT IMPROVING PATIENT CARE THROUGH BASIC AND TRANSLATIONAL RESEARCH. TRAINEES BENEFIT FROM A STRONG MENTORING PROGRAM AND A DEDICATED MENTORSHIP COMMITTEE, EXTENSIVE CORE SERVICES, EXPANDED CAPABILITIES IN EPIDEMIOLOGY AND BIOSTATISTICS, INSTITUTIONAL PATIENT REGISTRIES, AND NEWLY CREATED REGENERATIVE MEDICINE AND GENOMICS RESEARCH CENTERS THAT TRAVERSE OUR RESEARCH AND CLINICAL DEPARTMENTS. A 10+ YEAR COLLABORATION WITH WEILL CORNELL MEDICINE (WCM), AND ESPECIALLY THE WCM CLINICAL AND TRANSLATIONAL SCIENCE CENTER (CTSC), PROVIDES FORMAL COURSEWORK, SEMINARS AND SYMPOSIA. IN SUMMARY, OUR RICH RESOURCES WILL BE LEVERAGED AND CHOREOGRAPHED ACROSS OUR PRE- AND POST-DOCTORAL TRAINING PROGRAM TO PROVIDE A UNIQUE TRAINING EXPERIENCE AND POSITION OUR TRAINEES TO DEVELOP SUCCESSFUL INDEPENDENT CAREERS IN THE ORTHOPAEDIC SCIENCES.

MECHANISM OF HARD TISSUE MINERALIZATION

OSTEOGENESIS AND REPAIR IN LIVING INTACT BONE

LYMPHOID TISSUE MICROVESSEL GROWTH

SIGNALING CASCADES IN HUMORAL IMMUNITY AND AUTOIMMUNITY

ENHANCEMENT OF IMPLANT OSSEOINTEGRATION

DESIGNING A MENISCAL SUBSTITUTE THROUGH AN INTEGRATED EXPERIMENTAL COMPUTATIONAL

LANGERHANS CELLS AND LYMPHATIC REGULATION IN IMMUNITY - IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), SKIN PATHOPHYSIOLOGY IS LINKED TO AUTOIMMUNITY. PATIENTS ARE PHOTOSENSITIVE, ABLE TO DEVELOP INFLAMMATORY SKIN LESIONS WITH EVEN AMBIENT ULTRAVIOLET RADIATION (UVR) EXPOSURE, WHICH CAN ALSO INDUCE SYSTEMIC DISEASE FLARES. OUR LONG-TERM GOAL IS TO UNDERSTAND MECHANISMS THAT LINK CUTANEOUS PHOTOSENSITIVITY WITH SYSTEMIC AUTOIMMUNITY, FOCUSING ON SKIN REGULATION AND THE CONSEQUENCES ON DRAINING LYMPH NODE FUNCTION. DERMAL LYMPHATIC VESSELS SERVE TO REMOVE INTERSTITIAL FLUID FROM SKIN AND REGULATE DOWNSTREAM LYMPH NODES, THE LATTER BY TRANSPORTING ANTIGENS AND CELLS AND BY DIRECTLY REGULATING MIGRATING IMMUNE CELLS. WE RECENTLY SHOWED THAT COMPROMISED LYMPHATIC FLOW CONTRIBUTES TO INCREASED SKIN INFLAMMATION AND LYMPH NODE B CELL RESPONSES IN LUPUS. THIS PROPOSAL INVESTIGATES MECHANISMS THAT REGULATE LYMPHATIC FUNCTION TO BETTER UNDERSTAND THE BASIS OF THE DYSFUNCTION IN DISEASE. PRELIMINARY DATA SHOW THAT LANGERIN-DTA (LANG-DTA) MICE CONSTITUTIVELY LACKING LANGERHANS CELLS (LCS) HAVE REDUCED DERMAL LYMPHATIC ENDOTHELIAL CELL (LEC) NUMBERS, ALTERED LEC PHENOTYPE, AND POOR LYMPHATIC FLOW, REFLECTING LEC APOPTOSIS AND FAILURE TO DEVELOP POSTNATALLY FROM 3 WEEKS OF AGE ON. IN ADULTHOOD, LCS ARE REQUIRED TO MAINTAIN DERMAL LEC NUMBERS DURING ULTRAVIOLET RADIATION-INDUCED INFLAMMATION. THE POSTNATAL LYMPHATIC EXPANSION DEPENDS ON BOTH VASCULAR ENDOTHELIAL GROWTH FACTOR-C (VEGF-C) AND PLACENTAL GROWTH FACTOR (PGF). KERATINOCYTES ARE MAJOR VEGF-C EXPRESSORS IN SKIN AND LCS BIND VEGF-C IN A MANNER THAT IS REDUCED WITH ANTI-LANGERIN OR WITH MYELOID LOSS OF HEPARAN SULFATE 2-O-SULFOTRANSFERASE 1 (HS2ST1). WE FURTHER SHOW THAT RESTORING POSTNATAL LYMPHATIC EXPANSION WITH VEGF-C+PGF REDUCES THE KNOWN INCREASED T CELL PRIMING IN RESPONSE TO A CONTACT SENSITIZER IN LANG-DTA MICE. THE INCREASED T CELL PRIMING IS ASSOCIATED WITH REDUCED LEC IDO1 EXPRESSION AND INCREASED MATURATION OF SKIN-DERIVED MIGRATORY DENDRITIC CELLS, SUGGESTING THAT DYSREGULATION OF THE LC-LEC AXIS COMPROMISES THE IMMUNE REGULATORY FUNCTION OF LECS. TOGETHER, THE DATA LEAD TO A MODEL OF AN LC-LEC AXIS WHEREBY LCS ARE “LICENSED” TO REGULATE POSTNATAL LEC DEVELOPMENT THAT FUNCTIONS TO REGULATE IMMUNITY IN ADULTHOOD, AND THIS AXIS IS RECAPITULATED DURING INFLAMMATION IN ADULTHOOD. WE HYPOTHESIZE THAT LCS ARE LICENSED FOR LYMPHATIC REGULATION BY KERATINOCYTE PROVISION OF VEGF-C AND LC LANGERIN AND HS2ST1, PRESUMABLY TO BIND AND TRANSPORT VEGF-C TO THE DERMAL LYMPHATICS, THAT THIS LC-MEDIATED REGULATION SHAPES TOLEROGENIC PROGRAMS IN LECS, AND THAT A DYSFUNCTIONAL LC-LEC AXIS CONTRIBUTES TO LYMPHATIC DYSFUNCTION IN SLE. THE AIMS ARE TO 1) DELINEATE THE DETERMINANTS OF LC LICENSING FOR LYMPHATIC REGULATION, 2) IDENTIFY THE TOLEROGENIC PROGRAMS IN LECS THAT ARE REGULATED BY LCS, AND 3) UNDERSTAND THE EXTENT TO WHICH LYMPHATIC DYSFUNCTION IN SLE MODELS IS RELATED TO A DYSFUNCTIONAL LC-LEC AXIS. THIS STUDY WILL HELP US UNDERSTAND HOW SKIN FUNCTION MODULATES IMMUNITY ACROSS TIME AND IN DISEASE.

MECHANISMS OF INFLAMMATORY OSTEOBLASTOGENESIS AND BONE FORMATION - THE INTEGRITY OF THE ADULT SKELETON IS MAINTAINED BY BALANCED REMODELING BETWEEN OSTEOCLAST-MEDIATED BONE RESORPTION AND OSTEOBLAST/OSTEOCYTE-MEDIATED BONE FORMATION. HOWEVER, EXCESSIVE BONE LOSS BUT LIMITED BONE FORMATION OFTEN OCCUR IN MANY CHRONIC INFLAMMATORY SETTINGS, SUCH AS RHEUMATOID ARTHRITIS (RA) AND PERIODONTITIS. IN CONTRAST TO THE EXTENSIVE STUDIES ON OSTEOCLASTIC BONE RESORPTION, THE DEREGULATED OSTEOBLASTOGENESIS AND DAMAGED BONE FORMATION, ESPECIALLY IN INFLAMMATORY CONDITIONS, ARE MUCH LESS UNDERSTOOD. THERE ARE NO KNOWN EFFECTIVE THERAPIES TO IMPROVE BONE FORMATION IN RA CURRENTLY. WE RECENTLY IDENTIFIED CONSTITUTIVE TYPE-I INTERFERON (IFN-I) RESPONSE ACTIVITY IN OSTEOBLASTS, EVIDENCED BY THE CONSTITUTIVE EXPRESSION OF TYPE I IFN-STIMULATED/RESPONSE GENES (ISGS), WHICH IS A NEWLY RECOGNIZED CELLULAR SIGNATURE OF OSTEOBLASTS. IT IS INTRIGUING THAT OSTEOBLASTS, A NON-TYPICAL IMMUNE CELL TYPE, PRESENT IFN-I RESPONSE SIGNATURE IN THE ABSENCE OF INFECTION. WE FOUND THAT THE CONSTITUTIVE IFN-I RESPONSE PLAYS AN INHIBITORY ROLE IN OSTEOBLAST DIFFERENTIATION AND BONE FORMATION WITH GENETIC EVIDENCE, WHICH UNDERSCORES ITS BIOLOGICAL SIGNIFICANCE IN OSTEOBLASTOGENESIS AND BONE HOMEOSTASIS. ISGS ARE USUALLY THE INDICATORS AND EFFECTORS OF IFN-I PATHWAY/RESPONSE. AMONG THE ISGS, WE IDENTIFIED EIF2AK2 (ENCODING EUKARYOTIC TRANSLATION INITIATION FACTOR 2- ALPHA KINASE 2) AS AN IMPORTANT INHIBITOR OF OSTEOGENESIS. IMPORTANTLY, EIF2AK2 IS A CENTRAL REGULATOR OF IFN-I RESPONSE IN OSTEOBLASTIC INHIBITION. EIF2AK2-/- MICE EXHIBIT SIGNIFICANTLY HIGH BONE MASS WITH PROMINENTLY INCREASED OSTEOBLASTIC BONE FORMATION IN VIVO. OUR DATA INCLUDING RNASEQ RESULTS FURTHER REVEAL A NOVEL PATHWAY MEDIATED BY IFN-I-EIF2AK2-Β-CATENIN IN THE REGULATION OF OSTEOBLASTOGENESIS. MOREOVER, INFLAMMATORY CYTOKINE TNFΑ SIGNIFICANTLY ENHANCES THE CONSTITUTIVE IFN-I RESPONSE IN OSTEOBLASTS, INDICATING A NOVEL MOLECULAR MECHANISM BY WHICH TNFΑ RESTRAINS BONE FORMATION. WE ALSO FOUND A DRASTIC AGING EFFECT OF THE CONSTITUTIVE IFN-I RESPONSE ON BONE MASS. BASED ON OUR PRELIMINARY RESULTS, IN THIS APPLICATION, WE WILL FURTHER 1) INVESTIGATE THE MECHANISMS BY WHICH THE CONSTITUTIVE IFN-I RESPONSE SUPPRESSES OSTEOBLASTOGENESIS; 2) INVESTIGATE HOW THE EFFECTS OF CONSTITUTIVE IFN-I RESPONSE IN OSTEOBLASTS/OSTEOCYTES ON BONE HOMEOSTASIS ARE INFLUENCED BY AGING IN BOTH MALES AND FEMALES; AND 3) INVESTIGATE THE FUNCTIONAL IMPORTANCE OF CONSTITUTIVE IFN-I RESPONSE IN OSTEOBLASTS/OSTEOCYTES IN INFLAMMATORY ARTHRITIC ANIMAL MODELS WITH OSTEOGENIC DEFECTS. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL SHIFT THE CURRENTLY ESTABLISHED PARADIGM IN IMMUNOLOGY FOR IFN-I RESPONSE TO A NEW PARADIGM IN BONE WITH DISTINCT FUNCTION AND MECHANISMS. IDENTIFICATION OF PREVIOUSLY UNRECOGNIZED MECHANISMS IN OSTEOGENIC INHIBITION WILL PROVIDE A RATIONAL FRAMEWORK FOR DEVELOPING NEW THERAPEUTIC APPROACHES TO ENHANCING OSTEOBLAST/OSTEOCYTE-MEDIATED BONE FORMATION/REPAIR IN SKELETAL DISEASES.

OSTEOCLAST PROGRAMMING AND REPROGRAMMING DURING OSTEOCLASTOGENESIS - ABSTRACT OSTEOCLASTS ARE LARGE, MYELOID-DERIVED MULTINUCLEATED CELLS PRIMARILY RESPONSIBLE FOR BONE RESORPTION. DYSREGULATION OF OSTEOCLAST DIFFERENTIATION CAN RESULT IN NET BONE RESORPTION AND IS KEY TO THE PATHOPHYSIOLOGY OF OSTEOPOROSIS, RHEUMATOID ARTHRITIS, AND LYTIC BONE METASTASIS. DESPITE SUBSTANTIAL ADVANCES IN THE IDENTIFICATION OF OSTEOCLAST MASTER REGULATORS, DEVELOPING THERAPEUTIC INTERVENTIONS FOR PATHOLOGIC OSTEOCLASTS HAS BEEN CHALLENGING DUE TO OFF-TARGET/SIDE EFFECTS. THUS, WE HYPOTHESIZED THAT A BETTER UNDERSTANDING OF OSTEOCLAST- SPECIFIC REGULATION CAN DIRECTLY LEAD TO THE DEVELOPMENT OF NOVEL OSTEOCLAST-SPECIFIC THERAPEUTIC STRATEGIES TO PREVENT OR HALT THE DISEASE’S PROGRESSION. OSTEOCLAST GENE TRANSCRIPTION IS HIGHLY ORGANIZED AND IS UNDERSTOOD TO BE DRIVEN BY ENHANCERS. IN ORDER TO IDENTIFY OSTEOCLAST-SPECIFIC EPIGENETIC PROGRAMS, WE FOCUSED ON SUPER- ENHANCERS. SUPER-ENHANCERS ARE CLUSTERS OF ENHANCERS THAT HAVE BEEN PROPOSED TO REGULATE KEY GENES OF CELLULAR IDENTITY AND FATE. WE FOUND 348 SUPER-ENHANCERS IN HUMAN OSTEOCLASTS THROUGH GENOME-WIDE ANALYSIS OF DIFFERENTIAL TRANSCRIPTIONAL AND EPIGENETIC REGULATION. WE ALSO FOUND THAT RANKL-REGULATED SUPER-ENHANCERS ARE SPECIFIC TO OSTEOCLASTS BUT DO NOT PRESENT IN OTHER TYPES OF CELLS. TO INCREASE THE FEASIBILITY OF TARGETING THESE SUPER-ENHANCERS, WE IDENTIFIED A NEW CLASS OF NON-CODING RNAS TRANSCRIBED FROM SUPER-ENHANCERS (NAMED OSLINCS) IN HUMAN OSTEOCLASTS AND PROVIDED EVIDENCE SHOWING THE ROLE OF OSLINCS IN GENE EXPRESSION AND OSTEOCLASTOGENESIS. IN THIS APPLICATION, WE AIM TO CHARACTERIZE OSTEOCLAST-SPECIFIC PROGRAMS BY INVESTIGATING OSLINCS’ ACTION AND BIOGENESIS IN HEALTH AND DISEASE. OUR SPECIFIC AIMS ARE TO 1) DETERMINE THE UNDERLYING MECHANISM OF OSLINCS’ FUNCTION, 2) ELUCIDATE THE MECHANISMS BY WHICH THE EXPRESSION OF OSLINCS IS REGULATED, AND 3) IDENTIFY OSLINCS THAT ARE DIFFERENTIALLY REGULATED BETWEEN HEALTHY CONTROLS AND PATIENTS WITH RHEUMATOID ARTHRITIS (RA). WE ANTICIPATE THAT THE NEW INFORMATION GENERATED BY THIS PROPOSAL WILL ILLUMINATE OSTEOCLAST-SPECIFIC REGULATION AND ALLOW US TO EXPLORE THE IMPLEMENTATION OF NOVEL, TARGETED THERAPEUTIC APPROACHES FOR AMELIORATING THE COURSE OF PATHOLOGICAL BONE LOSS.

MUSCULOSKELETAL RESEARCH TRAINING

GLUCOCORTICOID RECEPTOR-MEDIATED REPRESSION OF PRO-INFLAMMATORY GENES IN RHEUMATOID ARTHRITIS

INTERFERON IN SYSTEMIC LUPUS ERYTHEMATOSUS

SLE-AWARE: SLE-- A WINDOW INTO APOL1 REGULATION AND EXPRESSION - PROJECT SUMMARY/ABSTRACT BACKGROUND: APPROXIMATELY 13% OF AFRICAN AMERICANS (AA), WHO SUFFER DISPROPORTIONATELY FROM KIDNEY AND CARDIOVASCULAR DISEASE, CARRY TWO COPIES OF THE APOLIPOPROTEIN L1 (APOL1) GENE RISK VARIANTS (RV). THESE RVS CONTRIBUTE TO RENAL AND CARDIOVASCULAR MORTALITY, YET NO THERAPIES ADDRESS GENE MECHANISM. IN CELL CULTURE AND ANIMAL MODELS, INFLAMMATORY CYTOKINES INCREASE APOL1 EXPRESSION AND WORSEN APOL1 HIGH-RISK GENOTYPE (HRG) RELATED INJURY. THE DEGREE TO WHICH IMMUNE ACTIVATION AND RESULTANT INCREASED APOL1 EXPRESSION SYNERGIZES WITH APOL1 GENOTYPE TO PRECIPITATE HUMAN DISEASE, SUCH AS LUPUS NEPHRITIS, IS NOT UNDERSTOOD. WE WILL TEST THE OVERARCHING HYPOTHESIS THAT APOL1 HRG SLE PATIENTS EXPERIENCE WORSENED DISEASE FEATURES BOTH DUE TO SLE INFLAMMATORY MEDIATORS WHICH INDUCE GENE EXPRESSION AND TO PROTEIN CODING CHANGES CARRIED ON THE VARIANT ALLELE. IMPORTANTLY, AN UNPRECEDENTED NUMBER OF BIOLOGIC THERAPIES ARE AVAILABLE TO PHARMACOLOGICALLY MODULATE IMMUNE PATHWAYS. THEREFORE UNDERSTANDING THE RELATIVE CONTRIBUTION OF SPECIFIC IMMUNE PATHWAYS TO APOL1 HRG ASSOCIATED DISEASE MAY OFFER NEW TREATMENT OPPORTUNITIES IN THIS SENSITIVE POPULATION. PRELIMINARY DATA: IN OUR UNIQUE, AA SLE COHORT AND GHANAIAN REPLICATION COHORT, OUR GROUP REPRODUCIBLY IDENTIFIED APOL1 HRG ASSOCIATED TRAITS INCLUDING HYPERTENSION, RENAL DYSFUNCTION, AND EARLY ATHEROSCLEROSIS. BOTH IN SLE MONOCYTES AND PRIMARY MONOCYTE CELL CULTURES, WE IDENTIFIED SLE-RELEVANT IMMUNE STIMULI THAT INDUCE APOL1 EXPRESSION. WE SHOWED THAT HRG MONOCYTES IN RESPONSE TO HIGH APOL1 EXPRESSION EXHIBIT MITOCHONDRIAL DYSFUNCTION. THESE FINDINGS HAVE CLINICAL IMPLICATIONS AS THEY SUPPORT A STRATEGY AIMED AT REDUCING IMMUNE ACTIVATION TO MITIGATE APOL1 EXPRESSION AND RESULTANT HRG ASSOCIATED DISEASE FEATURES. METHODS: TO UNDERSTAND APOL1 IMMUNE REGULATION, WE WILL ANALYZE SLE PATIENT MONOCYTE TRANSCRIPTIONAL PROFILES BY RNA-SEQ TO ASSESS IMMUNE PATHWAY ACTIVATION. APOL1 GENOTYPE, APOL1 TRANSCRIPTIONAL EXPRESSION, AND IMMUNE PATHWAY SCORES WILL BE TESTED FOR ASSOCIATION WITH CLINICAL OUTCOMES, INDEPENDENTLY AND IN INTERACTION MODELS. WE WILL DETERMINE WHETHER INCREASED APOL1 EXPRESSION SYNERGIZES WITH RISK GENOTYPE, AND WHICH IMMUNE SYSTEM PATHWAYS REFLECTED IN THE RNA-SEQ DATA ARE ASSOCIATED WITH APOL1 EXPRESSION. WE WILL VALIDATE THE HUMAN TRANSCRIPTIONAL ANALYSIS USING IN-VITRO MONOCYTE CELL CULTURE MODELS. OBJECTIVES AND CAREER DEVELOPMENT: THIS PROPOSAL LEVERAGES UNIQUE CLINICAL AND LABORATORY RESOURCES, AND HIGHLY COLLABORATIVE ENVIRONMENT BETWEEN EXPERTS IN STATISTICAL GENETICS, FUNCTIONAL GENOMICS, IMMUNOLOGY, CARDIOLOGY, AND RHEUMATOLOGY. IT WILL LAY THE GROUNDWORK TO PROPOSE FUTURE LARGER-SCALE STUDIES DESIGNED TO TARGET SPECIFIC IMMUNE PATHWAYS IN APOL1 HRG PATIENTS. FURTHERMORE, IT WILL ALLOW THE PI TO BECOME AN EXPERT IN THE FUNCTIONAL GENOMICS OF AUTOIMMUNE DISEASE AND RELATED KIDNEY AND VASCULAR COMORBIDITIES, GENETIC MODELING IN COMPLEX CLINICAL TRAITS, AND INNOVATIVE LABORATORY AND COMPUTATIONAL TECHNIQUES. THUS, THIS WILL PROVIDE A FRAMEWORK FOR THE PI’S INDEPENDENT TRANSLATIONAL CAREER.

INTERFERON REGULATION IN SYSTEMIC LUPUS

IMPROVING THE PERFORMANCE OF ELBOW RECONSTRUCTION

THE INTERACTION OF MECHANICAL LOAD AND INFLAMMATION IN TENDON-BONE HEALING

NEGATIVE REGULATION OF OSTEOCLASTOGENESIS - MANY PATHOLOGICAL CONDITIONS ASSOCIATED WITH EXCESSIVE BONE LOSS ARE CHARACTERIZED BY INCREASED GENERATION OF OSTEOCLASTS, MYELOID LINEAGE CELLS THAT RESORB BONE. THE LONG TERM GOALS OF THIS PROJECT ARE TO ELUCIDATE MOLECULAR PATHWAYS AND MECHANISMS THAT REGULATE MYELOID CELL FUNCTION AND OSTEOCLASTOGENESIS UNDER PATHOLOGICAL INFLAMMATORY CONDITIONS, WITH THE ASSOCIATED GOAL OF USING THIS INFORMATION TO DEVELOP NEW THERAPEUTIC APPROACHES TO SUPPRESS PATHOLOGICAL BONE RESORPTION. INFLAMMATION IS AN IMPORTANT DRIVER OF PATHOLOGICAL BONE LOSS IN DISEASES SUCH AS RHEUMATOID ARTHRITIS AND INFECTIONS. PATHOLOGICAL INFLAMMATION-ASSOCIATED BONE LOSS IS RESISTANT TO STANDARD ANTI-RESORPTIVE THERAPIES; THUS, DEVELOPMENT OF NEW TREATMENTS REPRESENTS AN IMPORTANT UNMET MEDICAL NEED. IN THE PREVIOUS CYCLE OF THIS APPLICATION, WE DEFINED EPIGENETIC AND METABOLIC MECHANISMS BY WHICH INFLAMMATORY CYTOKINES, INTERFERON- (IFN-) AND HYPOXIA REGULATE OSTEOCLASTOGENESIS. WE TESTED THE PATHOPHYSIOLOGICAL IMPORTANCE OF THESE MECHANISMS IN MODELS OF INFLAMMATORY BONE LOSS INCLUDING ARTHRITIS, IMPLANT LOOSENING, SUPRACALVAREAL OSTEOLYSIS, AND ORTHOPEDIC PERIPROSTHETIC JOINT INFECTION (PJI). PJI IS A DEVASTATING COMPLICATION OF JOINT REPLACEMENT SURGERY THAT IS RESISTANT TO TREATMENT AND A MAJOR CAUSE OF MORBIDITY, AND EVEN MORTALITY, IN ORTHOPEDICS. ONE ASPECT OF PJI IS BIOFILM-ASSOCIATED INFECTION AT THE BONE- IMPLANT INTERFACE WHICH RESULTS IN BOSS LOSS AND IMPLANT LOOSENING. USING A CLINICALLY RELEVANT TIBIAL IMPLANT MODEL OF PERSISTENT BIOFILM-ASSOCIATED STAPHYLOCOCCUS AUREUS PJI, WE OBSERVED BONE LOSS AND FAILURE OF OSSEOINTEGRATION. THIS WAS ASSOCIATED WITH SUSTAINED INFLAMMATION AT SITES OF INFECTION, BUT ADAPTIVE IMMUNE T CELLS WERE SUPPRESSED. ADVANCING THE LITERATURE DEMONSTRATING MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS) THAT SUPPRESS T CELLS IN S. AUREUS INFECTIONS, WE NEWLY IDENTIFIED EXPRESSION OF INHIBITORY GENES IN THE SETTING OF A STRONG IFN- SIGNATURE, AN OSTEOCLASTOGENIC PROGRAM SELECTIVELY AT THE BONE-IMPLANT INTERFACE, AND ALTERED MYELOPOIESIS IN THE DISTAL BONE MARROW. INHIBITORY GENE EXPRESSION WAS MARKEDLY HIGHER IN TISSUE ADJACENT TO THE IMPLANT AND BIOFILM, RELATIVE TO SOFT TISSUES INFECTED WITH PLANKTONIC PHASE S. AUREUS. BASED ON THESE RESULTS, OUR OVERARCHING HYPOTHESIS IS THAT S. AUREUS PJI INFECTION INDUCES SUSTAINED INFLAMMATION THAT DRIVES OSTEOCLASTOGENESIS, BUT CONCOMITANTLY INDUCES FEEDBACK INHIBITORY MECHANISMS THAT SUPPRESS ADAPTIVE IMMUNITY AND ATTENUATE CLEARANCE OF INFECTION, RESULTING IN SUBSTANTIAL MORBIDITY. WE PROPOSE THAT GREATER UNDERSTANDING OF THE INFLAMMATORY AND BONE MARROW RESPONSES THAT DRIVE OSTEOCLASTOGENESIS, AND OF FEEDBACK MECHANISMS THAT SUPPRESS THE ADAPTIVE IMMUNE RESPONSE TO PJI, WILL PROVIDE KNOWLEDGE THAT CAN BE USED TO DEVELOP NEW APPROACHES TO SUPPRESS PATHOLOGIC BONE RESORPTION AND TO DEVELOP ADJUVANT IMMUNOTHERAPIES TO HELP CLEAR THIS DEVASTATING CONDITION.

MECHANISM OF APL ANTIBODY-INDUCED PREGNANCY LOSS

TNF-ALPHA BLOCKADE WITH CERTOLIZUMAB TO PREVENT PREGNANCY COMPLICATIONS IN HIGH-RISK PATIENTS WITH APS

RHEUMATOLOGY RESEARCH TRAINING PROGRAM

TRIAL OF ASTHMA PATIENT EDUCATION IN THE EMERGENCY ROOM

CROSS-TALK BETWEEN ESTROGEN AND T CELLS MEDIATED PATHWAYS IN LUPUS PATHOGENESIS

TRIAL OF ASTHMA SELF-MANAGEMENT EDUCATION IN PATIENTS WITH DEPRESSIVE SYMPTOMS

EVALUATION OF AN MRI BIOMARKER FOR MENISCAL REPAIR

REGULATION OF OSTEOCLASTOGENESIS AND ARTHRITIC BONE RESORPTION BY RBP-J

NEGATIVE REGULATION OF OSTEOCLASTOGENESIS BY INFLAMMATORY SIGNALS

IN VITRO INITIATION OF BIOLOGICAL CALCIFICATION

REFERRAL PATTERNS AND RISK OF EARLY REVISION AFTER PRIMARY TOTAL JOINT ARTHROPLAS

MRI BONE TEXTURE: A NOVEL BIOMARKER FOR ASSESSMENT OF BONE QUALITY AND PREDICTION OF COMPLICATIONS IN PATIENTS HAVING SPINE FUSION SURGERY - PROJECT SUMMARY SPINE FUSION SURGERY IS ONE OF THE MOST COMMON, AND COMPLEX, ORTHOPEDIC PROCEDURES. COMPLICATIONS OCCUR IN OVER 30% OF CASES, HIGHLIGHTING THE NEED TO IDENTIFY MODIFIABLE FACTORS ASSOCIATED WITH THESE NEGATIVE SEQUELAE. BONE QUALITY IS A CRITICAL DETERMINANT OF POST-OPERATIVE OUTCOMES, AS STABILITY OF HARDWARE IN BONE AND DE NOVO BONE FORMATION ARE REQUIRED FOR SUCCESSFUL FUSION. DESPITE THE IMPORTANCE OF BONE QUALITY TO POST-OPERATIVE OUTCOMES, THERE ARE LIMITED TOOLS FOR PRE-OPERATIVE DETECTION OF ABNORMAL BONE IN CANDIDATES FOR FUSION. THE MOST COMMON CLINICAL TOOL FOR SKELETAL ASSESSMENT, DUAL ENERGY X-RAY ABSORPTIOMETRY (DXA), IS SUBJECT TO ARTIFACT FROM SPINAL ABNORMALITIES AND INFREQUENTLY PERFORMED FOR PRE-OPERATIVE EVALUATION. HIGH RESOLUTION PERIPHERAL QCT (HRPQCT) CAN DETECT PRE-OPERATIVE SKELETAL ABNORMALITIES AND PREDICT COMPLICATIONS AFTER FUSION BUT IS A RESEARCH TOOL NOT AVAILABLE IN CLINICAL PRACTICE. IN CONTRAST, MRI IS ROUTINELY PERFORMED PRIOR TO FUSION, FOR DIAGNOSIS OF SPINAL DISEASE AND SURGICAL PLANNING, MAKING AN MRI-BASED TECHNIQUE IDEAL TO SCREEN FOR PRE-OPERATIVE SKELETAL DEFICITS. OUR GROUP HAS RECENTLY DEVELOPED A NOVEL METHOD TO EVALUATE BONE QUALITY USING STANDARD, CLINICALLY ACQUIRED MRIS WHICH ANALYZES THE IRREGULARITY, OR HETEROGENEITY, OF TRABECULAR BONE TEXTURE. IN PRIOR WORK, WE FOUND THAT POSTMENOPAUSAL WOMEN WITH FRACTURES HAD GREATER HETEROGENEITY OF BONE TEXTURE THAN AGE- MATCHED CONTROLS. THE PROPOSED STUDY WILL ASSESS MRI TRABECULAR BONE TEXTURE AS A NEW TECHNIQUE TO DETECT POOR BONE QUALITY, PREDICT COMPLICATIONS, AND TRACK POST-OPERATIVE SKELETAL CHANGES IN PATIENTS UNDERGOING SPINAL FUSION. WE HYPOTHESIZE THAT PRE-OPERATIVE MRI BONE TEXTURE WILL RELATE TO VOLUMETRIC BMD (VBMD) AND MICROARCHITECTURE BY HRPQCT AND WILL PREDICT SKELETAL COMPLICATIONS AFTER SURGERY. POST-OPERATIVE CHANGES IN MRI BONE TEXTURE WILL RELATE TO BASELINE PATIENT CHARACTERISTICS AND CLINICAL POST-OPERATIVE TREATMENT REGIMEN, INCLUDING USE OF ANABOLIC AGENTS. WE WILL PROSPECTIVELY ENROLL 100 PATIENTS HAVING LUMBAR SPINE FUSION AND FOLLOW THEM FOR ONE YEAR. BASELINE DXA, HRPQCT, AND OUR MRI-BASED METHOD WILL BE PERFORMED. MRIS WILL BE REPEATED AT 6 MONTHS POST-OPERATIVELY TO DETERMINE WHETHER EARLY CHANGES IN MRI BONE TEXTURE RELATE TO PATIENT CHARACTERISTICS, MEDICATION USE, AND PREDICT COMPLICATIONS. CT SCANS WILL BE PERFORMED AT ONE YEAR TO ASSESS SKELETAL COMPLICATIONS AND COMPLETENESS OF FUSION. THIS PROPOSAL AIMS TO: 1) INVESTIGATE THE RELATIONSHIP BETWEEN PRE-OPERATIVE MRI BONE TEXTURE AND HRPQCT MEASUREMENTS OF VBMD AND MICROARCHITECTURE; 2) INVESTIGATE WHETHER MRI BONE TEXTURE PREDICTS SKELETAL COMPLICATIONS AFTER FUSION; 3) ASSESS LONGITUDINAL CHANGES IN BONE TEXTURE AND THE CLINICAL FACTORS THAT INFLUENCE THESE CHANGES IN PATIENTS AFTER SPINE FUSION. THE LONG-TERM GOALS OF OUR RESEARCH ARE TO IMPROVE IDENTIFICATION OF PATIENTS AT HIGH RISK FOR POST-OPERATIVE COMPLICATIONS AND PROVIDE KNOWLEDGE THAT WILL ADVANCE FUTURE INTERVENTIONAL TRIALS. IN SUBSEQUENT WORK, WE PLAN TO EXTEND THIS TECHNIQUE TO OTHER ORTHOPEDIC POPULATIONS. ULTIMATELY, WE HOPE TO IMPROVE THE OUTCOMES OF PATIENTS UNDERGOING FUSION AND OTHER HIGH-RISK ORTHOPEDIC SURGERIES BY FACILITATING THE CREATION OF NEW PERI-OPERATIVE TREATMENT PARADIGMS.

CELL SORTER

RESURFACING DAMAGED ARTICULAR CARTILAGE TO REGAIN FUNCTIONAL PROPERTIES

ACTIVATION OF SYNOVIAL LINING FIBROBLASTS IN RHEUMATOID ARTHRITIS - PROJECT SUMMARY / ABSTRACT THIS PROPOSAL COMPRISES A FIVE-YEAR RESEARCH AND CAREER DEVELOPMENT PROGRAM FOR MELANIE H. SMITH, MD, PHD TO ACHIEVE INDEPENDENCE AS AN INVESTIGATOR AT THE INTERSECTION OF IMMUNOLOGY AND STROMAL BIOLOGY IN THE HUMAN SYNOVIUM. DR. SMITH IS AN ASSISTANT ATTENDING PHYSICIAN IN THE DIVISION OF RHEUMATOLOGY AT HOSPITAL FOR SPECIAL SURGERY (HSS) AND AN ASSISTANT ATTENDING PROFESSOR OF MEDICINE AT WEILL CORNELL MEDICAL COLLEGE IN NEW YORK CITY. SHE WILL CONDUCT RESEARCH UNDER THE JOINT MENTORSHIP OF DR. LAURA DONLIN (HSS) AND DR. ALEXANDER RUDENSKY (MEMORIAL SLOAN KETTERING CANCER CENTER) FOCUSED ON UNDERSTANDING THE ROLE OF SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS (RA). DR. SMITH WILL ENGAGE IN CAREER DEVELOPMENT ACTIVITIES INCLUDING DIDACTICS, WORKSHOPS IN GRANT WRITING AND LEADERSHIP, CONFERENCES, AND ACQUISITION OF TECHNICAL SKILLS AND SCIENTIFIC EXPERTISE. THESE ACTIVITIES WILL BE AUGMENTED THROUGH REGULAR INPUT FROM HER SCIENTIFIC ADVISORY TEAM. THIS TRAINING GRANT WILL GENERATE KEY SKILLS, DATA, AND PUBLICATIONS NECESSARY TO BECOME AN R01-FUNDED INDEPENDENT INVESTIGATOR. SYNOVIAL FIBROBLASTS (FLS) ARE THE MOST ABUNDANT RESIDENT CELLS IN THE SYNOVIUM AND ARE IMPLICATED IN MULTIPLE ASPECTS OF RA PATHOGENESIS. FLS SPECIFICALLY WITHIN THE SYNOVIAL LINING LAYER EXHIBIT EVIDENCE OF EXTENSIVE ACTIVATION AND ARE SELECTIVELY DEFINED BY ACCESSIBILITY OF AP-1 TRANSCRIPTION FACTOR MOTIFS. HERE WE WILL TEST THE CONTRIBUTIONS OF TOLL LIKE RECEPTOR (TLR) LIGANDS FROM THE SYNOVIAL FLUID, AND LOCAL EXPRESSION OF EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) LIGANDS IN ACTIVATING AP-1 IN FLS. THE CENTRAL HYPOTHESIS IS THAT THESE ACTIVATORS OF AP- 1, WHICH ARE PRESENT IN THE SYNOVIAL LINING MICROENVIRONMENT, PRIME LINING FLS TO MOUNT HEIGHTENED RESPONSES TO CYTOKINES DERIVED FROM INFILTRATING LEUKOCYTES, AND THAT AP-1 DRIVEN GENE EXPRESSION DRIVES FLS FUNCTIONAL SPECIALIZATION. WE WILL USE PRIMARY HUMAN SYNOVIAL FIBROBLASTS BOTH IN CULTURE AND DIRECTLY ISOLATED FROM SYNOVIAL TISSUE ALONG WITH SELECTIVE AGONISTS, TARGETED INHIBITORS AND CRISPR INTERFERENCE TO INTERROGATE THE MECHANISTIC BASIS AND FUNCTIONAL CONSEQUENCES OF THE FLS ACTIVATION OBSERVED SPECIFICALLY IN LINING FLS. THE SIGNIFICANCE OF THIS PROPOSAL LIES IN THE IDENTIFICATION OF KEY FACTORS RESPONSIBLE FOR FLS ACTIVATION THAT MAY FURTHER THE DEVELOPMENT OF FLS-TARGETED THERAPIES IN RA. THIS PROPOSAL IS INNOVATIVE IN THE INVESTIGATION OF NON-CYTOKINE DRIVEN PRIMING IN THE ESTABLISHMENT OF INFLAMMATORY MEMORY AND THE IDENTIFICATION OF THE SPECIFIC TRANSCRIPTION FACTORS INVOLVED USING ADVANCED SEQUENCING METHODS AS WELL AS CRISPR IN PRIMARY HUMAN FLS. LONG-TERM, DR. SMITH AIMS TO APPLY THE EXPERTISE GAINED IN THIS PROPOSAL TO IDENTIFY ENVIRONMENTAL AND INFLAMMATORY SIGNALS THAT MAINTAIN AND REGULATE SYNOVIAL INFLAMMATION TO IMPROVE TREATMENT OF RA.

DISCOVERING IMMUNE DRIVERS OF FIBROBLAST POLARIZATION ANDRECOVERY IN SYSTEMIC SCLEROSIS - PROJECT SUMMARY / ABSTRACT BACKGROUND: THIS PROPOSAL IS DESIGNED FOR DR. KIMBERLY LAKIN, MD, MS TO GROW TOWARD BECOMING AN INDEPENDENT INVESTIGATOR FOCUSED UPON CHARACTERIZING THE CLINICAL SIGNIFICANCE OF IMMUNE CELL-FIBROBLAST ASSOCIATIONS IN SYSTEMIC SCLEROSIS (SSC) SKIN. CURRENTLY, THERE ARE NO APPROVED TREATMENTS TO MANAGE BOTH SKIN AND INTERNAL ORGAN FIBROSIS CAUSED BY SYSTEMIC SCLEROSIS (SSC), A DEADLY AUTOIMMUNE DISEASE WITH A COMPLEX AND POORLY UNDERSTOOD PATHOPHYSIOLOGY INVOLVING INFLAMMATION AND EXCESS COLLAGEN PRODUCTION BY SKIN FIBROBLASTS. IN CLINICAL AND TRIAL SETTINGS, SOME PATIENTS IMPROVE, AT TIMES DRAMATICALLY, WHILE OTHERS DO NOT, POSSIBLY RELATED TO DISTINCT DISEASE PHASES WHEN CELLS ARE AMENABLE (OR NOT) TO TREATMENT. RELIABLE TOOLS ARE NEEDED TO INFORM INDIVIDUALIZED TREATMENT DECISIONS AND TRIAL ENROLLMENT. PRELIMINARY DATA BY DR. LAKIN AND HER MENTORS SUGGEST ASSESSMENTS OF FIBROBLAST ACTIVATION STATUS MAY YIELD SUCH A TOOL. PRELIMINARY DATA: USING PAIRED BIOLOGICAL (HISTOLOGY, GENE EXPRESSION) AND CLINICAL DATA FROM 24 INDIVIDUALS WITH DIFFUSE CUTANEOUS (DC)SSC, HISTOLOGIC ASSESSMENTS OF TWO, INVERSELY RELATED FIBROBLAST MARKERS (ASMA, CD34) WERE ASSOCIATED WITH CLINICAL SEVERITY AND PREDICTED THE SSC INFLAMMATORY GENE EXPRESSION SUBSET, USING MACHINE LEARNING METHODS. SAMPLES WITH INFLAMMATORY VS. NON-INFLAMMATORY FIBROBLASTS HAD INCREASED B CELLS AND TYPE I INTERFERON GENE SIGNATURE. A GENE SIGNATURE OF FIBROBLAST POLARIZATION (BY ASMA/CD34) WAS COMPUTED AND FOUND TO BE HIGHER AT BASELINE IN 52-WEEK CLINICAL IMPROVERS VS. NON-IMPROVERS. METHODS: FINE PHENOTYPE MAPPING OF DCSSC (N=105), PRESSC (VERY EARLY ONSET OF SSC; N=12) AND HEALTHY (N=12) SKIN WILL BE PERFORMED CROSS-SECTIONALLY. IMMUNE PATHWAYS AND CELL TYPES ASSOCIATED WITH ACTIVATED FIBROBLASTS WILL BE EVALUATED BY IMAGING MASS CYTOMETRY (IMC), DIGITAL CELL DECONVOLUTION, AND HISTOLOGY. IN A LONGITUDINAL ANALYSIS, BASELINE CLINICAL AND MOLECULAR FEATURES (HISTOLOGY SCORES; IMMUNE CELL AND FIBROBLAST POLARIZATION SIGNATURES) WILL BE TESTED AS INPUTS IN A MODEL TO PREDICT 52 WEEKS CLINICAL IMPROVEMENT. CAREER DEVELOPMENT: THE STUDY GOAL IS TO UNRAVEL IMMUNE CELL-FIBROBLAST INTERACTIONS IN SSC AND TO TEST A HISTOLOGY-DERIVED MODEL FOR CLASSIFYING PATIENTS MOST LIKELY TO CLINICALLY IMPROVE AT ONE YEAR. DR. LAKIN IS AN ASSISTANT ATTENDING PHYSICIAN AT HOSPITAL FOR SPECIAL SURGERY (HSS) AND ASSISTANT ATTENDING PROFESSOR OF MEDICINE AT WEILL CORNELL MEDICAL COLLEGE WITH ACCESS TO THE OUTSTANDING CORE SERVICES AT THESE INSTITUTIONS. SHE WILL CONDUCT PATIENT-ORIENTED RESEARCH UNDER THE MENTORSHIP OF DR. ROBERT SPIERA (HSS), AN EXPERT IN SSC CLINICAL RESEARCH, AND DR. DANA ORANGE (ROCKEFELLER), AN EXPERT IN THE USE OF BIOINFORMATIC APPROACHES TO DISCOVER PATIENT SUBSETS IN RHEUMATIC DISEASES. DR. LAKIN WILL ENGAGE IN EXPERIENTIAL AND FORMAL COURSEWORK TO ADVANCE HER BIOINFORMATICS, IMMUNOLOGY, AND SKIN IMAGING MASS CYTOMETRY SKILLS. THIS CAREER DEVELOPMENT AWARD WILL POSITION DR. LAKIN FOR SUCCESS IN HER OBJECTIVE TO BECOME AN R01-FUNDED INDEPENDENT INVESTIGATOR FOCUSED UPON IMPROVING SSC PATIENT CARE WHILE UNCOVERING KEY MECHANISMS OF SSC PATHOGENESIS.

MACROPHAGE AND FIBROBLAST CROSSTALK IN THE RA SYNOVIUM

ROLE OF CHOLESTEROL HOMEOSTASIS IN LUPUS PATHOGENESIS.

THE ROLE OF TRANSCRIPTIONAL COFACTOR GRIP1 IN MICROGLIA-DRIVEN NEUROINFLAMMATION

IMPACT OF THE DNA METHYLOME IN CHONDROCYTE HYPERTROPHY IN OSTEOARTHRITIS

ROLE OF ADAMS 9 AND 15 IN PROLIFERATIVE RETINOPATHY

NONCOLLAGENOUS PROTEIN INTERACTION IN BIOMINERALIZATION

SKIN-LYMPH NODE AXIS IN SLE - PROJECT SUMMARY PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) ARE PHOTOSENSITIVE, DEMONSTRATING AN INCREASED SKIN SENSITIVITY TO ULTRAVIOLET RADIATION (UVR) WHEREBY EVEN AMBIENT EXPOSURE TO SUNLIGHT CAN RESULT IN THE DEVELOPMENT OF INFLAMMATORY SKIN LESIONS. BEYOND THE SKIN, HOWEVER, UVR EXPOSURE CAN ALSO TRIGGER SYSTEMIC DISEASE FLARES, WITH INCREASED CIRCULATING AUTOANTIBODIES AND FURTHER INJURY OF END ORGANS. THE MECHANISMS BY WHICH UVR EXPOSURE AT THE SKIN CAN LEAD TO FLARES OF SYSTEMIC AUTOIMMUNITY ARE NOT WELL UNDERSTOOD. OUR LONG-TERM GOAL IS TO DELINEATE THE MECHANISMS THAT CONNECT PHOTOSENSITIVITY WITH SYSTEMIC DISEASE FLARES. IN THIS PROPOSAL, WE FOCUS ON THE COMMUNICATION BETWEEN SKIN AND THE IMMUNE SYSTEM. INTERSTITIAL FLUID FROM SKIN IS TRANSPORTED AS LYMPH VIA LYMPHATIC VESSELS TO DRAINING LYMPH NODES WHERE IMMUNE RESPONSES OCCUR AND CAN BE REGULATED. WITHIN THE LYMPH NODE, LYMPH FLUID IS CHANNELED FROM THE LYMPHATIC VESSELS INTO A CONDUIT SYSTEM THAT IS LINED BY FIBROBLASTIC RETICULAR CELLS (FRCS). BECAUSE OF THEIR LOCATION IN THE CONDUITS, FRCS ARE AMONG THE FIRST CELLULAR SENSORS OF SIGNALS FLOWING FROM THE SKIN. FRCS, IN TURN, ARE IN DIRECT CONTACT WITH DENDRITIC CELLS AND LYMPHOCYTES SITTING OUTSIDE THE CONDUITS AND PLAY CRITICAL ROLES IN REGULATING IMMUNE CELL FUNCTION. WE HAVE RECENTLY SHOWN THAT FRC-DERIVED CCL2 LIMITS PLASMABLAST RESPONSES IN HEALTHY (IE NON- LUPUS) MICE, INDICATING THAT FACTORS THAT MODULATE LYMPH NODE STROMAL CCL2 CAN POTENTIALLY IMPACT ANTIBODY OR AUTOANTIBODY GENERATION. WE NOW PRESENT PRELIMINARY DATA THAT, IN SLE MODEL MICE, CCL2-EXPRESSING FRCS HAVE AN ACTIVATED PHENOTYPE AND UVR EXPOSURE OF THE SKIN TRIGGERS BOTH A LOSS OF THESE FRCS AND INCREASED PLASMABLASTS IN SKIN-DRAINING LYMPH NODES. WE ALSO SHOW THAT NON-LESIONAL SKIN FROM LUPUS PATIENTS AND MURINE MODELS EXPRESS INTERFERON (IFN) SIGNATURES AND THAT PRE-TREATMENT WITH TYPE I IFN BLOCKADE REDUCES PHOTOSENSITIVITY IN TWO MURINE LUPUS MODELS THESE RESULTS TOGETHER SUGGEST THAT IFNS AND OTHER SIGNALS ACTIVATE AND SENSITIZE DRAINING LYMPH NODE CCL2-EXPRESSING FRCS, MAKING THEM MORE LIKELY TO DIE UPON UVR EXPOSURE, WITH CONSEQUENT INCREASES IN PLASMABLAST ACCUMULATION. WHILE OUR PRELIMINARY RESULTS ARE FOCUSED ON CCL2-EXPRESSING FRCS, OUR RESULTS MORE BROADLY SUGGEST A MODEL OF FRC PRIMING WHEREBY SIGNALS FROM EVEN NON-LESIONAL SKIN IN SLE CONSTITUTIVELY MODULATE FRCS IN DRAINING NODES, WHICH SHAPES FRC (AND THUS LYMPH NODE) RESPONSES TO ADDITIONAL STRESSORS SUCH AS UVR-INDUCED SKIN INFLAMMATION. HERE, WE PROPOSE THE HYPOTHESIS THAT THERE ARE SIGNALS SPECIFIC TO NON-LESIONAL SLE BUT NOT HEALTHY CONTROL SKIN THAT IMPACT FRC PHENOTYPE. WE WILL TEST THE HYPOTHESIS BY 1) ASSESSING THE ROLES OF IFNS AND LYMPH-BORNE SIGNALS IN MODULATING FRC AND LYMPH NODE FUNCTION IN VIVO, AND 2) DELINEATING THE SCOPE OF SIGNALS THAT ARE TRANSMITTED FROM NON-LESIONAL SKIN TO IMPACT FRCS IN HUMAN SLE. THESE STUDIES ARE ANTICIPATED TO PROVIDE INSIGHT INTO THE IMPORTANCE AND NATURE OF SKIN-LYMPH NODE COMMUNICATION, THE CONNECTION BETWEEN PHOTOSENSITIVITY AND SYSTEMIC DISEASE FLARES, AND NEW POTENTIAL THERAPEUTIC APPROACHES.

THE REGULATORY MECHANISMS OF OSTEOCLASTS - ABSTRACT OSTEOCLASTS ARE MULTINUCLEATED CELLS PRIMARILY RESPONSIBLE FOR BONE RESORPTION. THE DYSREGULATION OF OSTEOCLAST DIFFERENTIATION CAN RESULT IN EXCESSIVE BONE RESORPTION AND IS KEY TO THE PATHOPHYSIOLOGY OF BONE DISEASES, SUCH AS OSTEOPOROSIS, RHEUMATOID ARTHRITIS, AND LYTIC BONE METASTASIS. DESPITE SUBSTANTIAL ADVANCES IN ANTI- RESORPTIVE THERAPIES, DEVELOPING THERAPEUTIC INTERVENTIONS FOR PATHOLOGIC OSTEOCLASTS HAS BEEN CHALLENGING DUE TO THE OCCURRENCE OF RARE BUT SIGNIFICANT SIDE EFFECTS, DRUG TOLERANCE, AND PATIENT COMPLIANCE. OUR OVERARCHING HYPOTHESIS IS THAT THESE UNWANTED EFFECTS OF ANTIRESORPTIVE THERAPIES CAN BE LOWERED BY CELL-SPECIFIC TARGETING. OSTEOCLASTS ARE LONG-LIVE CELLS THAT CONTINUOUSLY ACQUIRE NEW NUCLEI BY FUSION WITH CIRCULATING OSTEOCLAST PRECURSOR CELLS (COCPS) AND ARE RECYCLED THROUGH THE FUSION AND FISSION CYCLE OF OSTEOMORPHS. THIS NEW CONCEPT OF LONG-LIVED OSTEOCLASTS HIGHLIGHTS THE IMPORTANT ROLE OF COCPS IN THE MANAGEMENT OF OSTEOCLASTS AND SUPPORTS THAT COCPS CAN SERVE AS AN OSTEOCLAST-SPECIFIC TARGET. WE HAVE IDENTIFIED AND CHARACTERIZED HUMAN COCPS AND FOUND A POSITIVE ASSOCIATION BETWEEN COCPS AND OSTEOPOROSIS. SORTED COCPS FROM THE BLOOD CIRCULATION HAVE A HIGHER OSTEOCLASTOGENIC POTENTIAL THAN OTHER MYELOID CELLS AND EFFECTIVELY DIFFERENTIATE INTO OSTEOCLASTS. MOREOVER, COCPS EXHIBIT DISTINCT MORPHOLOGY AND TRANSCRIPTOMIC SIGNATURES COMPARED TO OTHER MYELOID CELLS. COCPS ARE INVERSELY CORRELATED WITH BONE DENSITY AND ARE POSITIVELY ASSOCIATED WITH SERUM CTX1 IN POSTMENOPAUSAL WOMEN. INTRIGUINGLY, WE FOUND THAT NUCLEI IN MULTINUCLEAR OSTEOCLASTS ARE HETEROGENEOUS, AND ‘NEW VS OLD NUCLEI’ SHOW DISTINCT GENE EXPRESSION PROFILES. WE HYPOTHESIZE THAT COCPS REFLECT THE CHANGES IN BONE ENVIRONMENT AND THAT NEWLY INCORPORATED NUCLEI FROM COCPS REGULATE OSTEOCLAST ACTIVITY. IN THIS APPLICATION, WE AIM TO DETERMINE THE MECHANISMS UNDERLYING THE REGULATION OF COCPS. OUR SPECIFIC AIMS ARE 1) TO ELUCIDATE THE UNDERLYING MECHANISM BY WHICH COCPS ARE REGULATED AND 2) TO DETERMINE THE MECHANISM GOVERNING THE FUNCTION OF COCPS. WE ANTICIPATE THAT THE PROPOSED STUDY WILL PROVIDE NEW INSIGHTS INTO THE REGULATORY MECHANISM OF OSTEOCLAST FORMATION AND ENABLE US TO INVESTIGATE OSTEOCLAST-SPECIFIC REGULATION, ULTIMATELY LEADING TO IMPROVED MANAGEMENT OF THE COURSE OF PATHOLOGICAL BONE LOSS.

ESE 1 A NOVEL TRANSCRIPTIONAL REGULATOR OF CARTILAGE REMODELING

ADVERSE PREGNANCY OUTCOMES IN WOMEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS: IMPROVING AND VALIDATING RISK PREDICTION

THE MICROBIOME AS A RISK FACTOR FOR PERIPROSTHETIC JOINT INFECTION

SUBJECT-SPECIFIC MECHANISMS OF KNEE LAXITY

INHIBITION OF ROCK TO REVERSE T CELL DYSFUNCTION IN SLE

TABLET-BASED PHYSICAL ACTIVITY INTERVENTION FOR FRAIL AND PRE-FRAIL OLDER ADULTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS - PROJECT SUMMARY: ALTHOUGH ADULTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) NOW LIVE ROUTINELY TO 50 YEARS OF AGE AND BEYOND, THEIR RISK FOR ADVERSE HEALTH OUTCOMES IS HIGHER COMPARED TO OLDER ADULTS WITHOUT SLE DUE TO THE EFFECTS OF CUMULATIVE END-ORGAN DAMAGE. WHILE FRAILTY IS RECOGNIZED AS AN IMPORTANT MARKER OF VULNERABILITY IN SLE, LIMITED RESEARCH HAS FOCUSED ON TARGETED STRATEGIES TO IMPROVE CLINICALLY RELEVANT OUTCOMES IN FRAIL AND PRE-FRAIL OLDER ADULTS WITH SLE, SUGGESTING AN IMPORTANT UNMET NEED. IN KEEPING WITH STAGE 1 OF THE NATIONAL INSTITUTES OF HEALTH STAGE MODEL FOR BEHAVIORAL INTERVENTION DEVELOPMENT, THE GOAL OF THIS PROJECT IS FIRST TO ADAPT AND THEN TO PILOT TEST A SOCIAL COGNITIVE THEORY-BASED DIGITAL EXERCISE INTERVENTION FOR AGING ADULTS WITH SLE (≥50 YEARS OF AGE) STRATIFIED BY FRAILTY STATUS. THE FITTLE SENIOR SYSTEM (FSS) IS AN EVIDENCE-BASED DIGITAL EXERCISE PLATFORM WITH TEAM-DRIVEN SOCIAL SUPPORT FEATURES CREATED TO PROMOTE PHYSICAL ACTIVITY (PA) IN SEDENTARY OLDER ADULTS WITHOUT COMORBID CONDITIONS. IN THIS STUDY, THE FSS DIGITAL SOFTWARE PLATFORM WILL BE ADAPTED, LEVERAGING AN ESTABLISHED USER-CENTERED DESIGN APPROACH, TO MEET THE NEEDS OF THE SLE POPULATION, RESULTING IN FSS-SLE. MY OVERARCHING HYPOTHESIS IS THAT FSS-SLE WILL BE FEASIBLE FOR AND USABLE BY BOTH FRAIL AND PRE-FRAIL OLDER ADULTS WITH SLE. THE SPECIFIC PROJECT AIMS ARE TO: AIM 1: ADAPT FSS FOR FRAIL AND PRE-FRAIL ADULTS ≥50 YEARS OF AGE WITH SLE. SEMI-STRUCTURED INTERVIEWS WILL BE CONDUCTED WITH RHEUMATOLOGISTS AND PHYSICAL THERAPISTS, AS WELL AS FRAIL AND PRE-FRAIL AGING ADULTS WITH SLE TO GENERATE SUGGESTIONS FOR ADAPTATION OF THE FSS PROGRAM AND TO INCORPORATE KEY STAKEHOLDER PERSPECTIVES IN THE REFINEMENT PROCESS. AIM 2: CONDUCT HEURISTIC AND USABILITY ANALYSES OF THE ADAPTED FSS-SLE PROTOTYPE, ESSENTIAL COMPONENTS OF THE USER-CENTERED DESIGN PROCESS, TO IDENTIFY ANY UPFRONT FUNCTIONAL PROBLEMS (E.G., SYSTEM GLITCHES) WITH FSS- SLE PRIOR TO CONDUCTING A PILOT RANDOMIZED CONTROLLED TRIAL (RCT). THE HEURISTIC ANALYSIS WILL BE BASED ON EXISTING EXERCISE GUIDELINES FOR FRAIL OLDER ADULTS AND DESIGN GUIDELINES FOR AGING ADULTS. THE USABILITY ANALYSIS WILL INCLUDE FRAIL AND PRE-FRAIL ADULTS ≥50 YEARS OF AGE WITH SLE. AIM 3: CONDUCT A PILOT DOUBLE BLIND RCT TO ASSESS FEASIBILITY, USABILITY, ACCEPTABILITY, AND PRELIMINARY EFFICACY OF FSS-SLE IN FRAIL AND PRE-FRAIL ADULTS ≥50 YEARS OF AGE WITH SLE. PARTICIPANTS WILL BE RANDOMIZED TO THE INTERVENTION OR A PA EDUCATIONAL CONTROL ARM. FEASIBILITY WILL BE EVALUATED BY RECRUITMENT AND RETENTION BASED ON FINDINGS FROM FSS. USABILITY AND ACCEPTABILITY WILL BE ASSESSED THROUGH SEMI-STRUCTURED INTERVIEWS AND VALIDATED INSTRUMENTS. PRELIMINARY EFFICACY WILL BE EXAMINED THROUGH CHANGE IN EXERCISE SELF-EFFICACY, A CRITICAL MEDIATOR OF PA BEHAVIOR, FROM BASELINE TO 6, 12, AND 24 WEEKS. THIS PROJECT WILL GENERATE PRELIMINARY DATA TO SUPPORT A MULTICENTER RCT OF FSS-SLE TARGETING FRAIL AND PRE-FRAIL OLDER ADULTS WITH SLE TO IMPROVE DISABILITY AND HEALTH-RELATED QUALITY OF LIFE IN THIS EXPANDING TARGET POPULATION.

PHYSICAL ACTIVITY BEHAVIORS AND READINESS FOR A DIGITAL HEALTH PHYSICAL ACTIVITY INTERVENTION INOLDER ADULTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS - PROJECT SUMMARY PHYSICAL ACTIVITY IS THOUGHT TO BE CRITICALLY IMPORTANT IN AGING ADULTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), WHO HAVE SIGNIFICANTLY HIGHER RATES OF CARDIOVASCULAR DISEASE AND MULTIMORBIDITY THAN THEIR PEERS WITHOUT SLE. DIGITAL PROGRAMMING REPRESENTS A VIABLE OPTION FOR PHYSICAL ACTIVITY PROMOTION IN OLDER ADULTS, INCLUDING THOSE WITH SLE. GIVEN THE UNIQUE CHARACTERISTICS OF OLDER ADULTS WITH SLE, SLE-SPECIFIC ADAPTATION IS CRITICAL TO MEETING THE NEEDS OF THE TARGET POPULATION. THE OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE PHYSICAL ACTIVITY LEVELS, IMPEDIMENTS TO AND FACILITATORS OF PHYSICAL ACTIVITY, AND READINESS TO PARTICIPATE IN A DIGITALLY-DELIVERED PHYSICAL ACTIVITY PROGRAM IN A SAMPLE OF AGING ADULTS WITH SLE (=50 YEARS OF AGE). THE CENTRAL TENET OF THIS PROPOSAL IS THAT DEFICITS IN PHYSICAL ACTIVITY BEHAVIORS AND MODIFIABLE RISK FACTORS FOR A SEDENTARY LIFESTYLE CAN BE MITIGATED THROUGH THE USE OF THE DIGITAL PHYSICAL ACTIVITY PROGRAM THAT ADDRESSES THE UNIQUE CHALLENGES FACED BY AGING ADULTS WITH SLE WHEN ATTEMPTING TO ENGAGE IN PHYSICAL ACTIVITY. DESIGN OF AN EFFICACIOUS PROGRAM WILL FIRST REQUIRE AN UNDERSTANDING OF THE DEFICITS IN PA BEHAVIORS AND MODIFIABLE RISK FACTORS FOR A SEDENTARY LIFESTYLE THAT ARE PRESENT IN THE TARGET POPULATION. PRELIMINARY DATA GATHERED THROUGH THE CURRENT PROPOSAL WILL INFORM ADAPTATION AND PILOT TESTING OF AN ESTABLISHED 12-WEEK DIGITALLY-DELIVERED PHYSICAL ACTIVITY PROGRAM WITH SOCIAL SUPPORT FEATURES. THE AIMS OF THIS PROPOSAL ARE AS FOLLOWS: AIM 1: TO ELICIT PERSPECTIVES OF ADULTS =50 YEARS OF AGE WITH SLE ON ENGAGEMENT IN PHYSICAL ACTIVITY, BARRIERS TO AND FACILITATORS OF PHYSICAL ACTIVITY, AND USE OF A DIGITAL PHYSICAL ACTIVITY PROGRAM. SEMI-STRUCTURED INTERVIEWS WILL ADDRESS FACTORS THAT INFLUENCE PHYSICAL ACTIVITY BEHAVIOR, AS WELL AS PERCEIVED USEFULNESS AND EASE OF USE OF AND LIKELINESS TO ENGAGE IN A DIGITAL PHYSICAL ACTIVITY PROGRAM. AIM 2: TO QUANTIFY PHYSICAL ACTIVITY LEVELS, BARRIERS TO AND FACILITATORS OF PHYSICAL ACTIVITY, AND READINESS FOR A DIGITAL PHYSICAL ACTIVITY PROGRAM IN A NATIONAL CROSS-SECTIONAL SAMPLE OF AGING ADULTS (I.E., =50 YEARS) WITH SLE. INFORMED BY THE RESULTS OF AIM 1, I WILL DEVELOP A QUESTIONNAIRE ADDRESSING BARRIERS TO AND FACILITATORS OF PHYSICAL ACTIVITY AND FACTORS IMPACTING USE OF A DIGITAL PHYSICAL ACTIVITY PROGRAM TO EVALUATE PREVALENCE OF THESE FACTORS IN A LARGER SAMPLE AND GUIDE FUTURE INTERVENTION ADAPTATION. USING VALIDATED SURVEYS, I WILL COLLECT ADDITIONAL DATA ON PHYSICAL ACTIVITY LEVELS, IMPEDIMENTS TO PHYSICAL ACTIVITY, AND READINESS FOR A DIGITAL HEALTH INTERVENTION. AT THE CONCLUSION OF THE STUDY, I WILL HAVE THE NECESSARY PRELIMINARY DATA TO ADAPT AND PILOT TEST A DIGITAL PHYSICAL ACTIVITY PROGRAM IN OLDER ADULTS WITH SLE THAT IS TAILORED TO THEIR NEEDS AND PREFERENCES, THUS EMPOWERING AGING ADULTS WITH SLE TO INCREASE THEIR PHYSICAL ACTIVITY LEVELS. THROUGH THIS WORK, I WILL BUILD A TRACK RECORD OF EXPERIENCE IN MULTIDISCIPLINARY AGING RESEARCH THAT WILL ALLOW ME TO IMPROVE THE HEALTH AND WELLBEING OF THIS VULNERABLE POPULATION.

DECONSTRUCTING DISPARITIES IN LUPUS PREGNANCIES - PROJECT SUMMARY / ABSTRACT IN A DISEASE LIKE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) THAT PRIMARILY AFFECTS WOMEN OF CHILDBEARING AGE, SOCIAL DETERMINANTS OF HEALTH (SDOH) AND CLINICAL FACTORS SIGNIFICANTLY IMPACT ADVERSE PREGNANCY OUTCOMES (APOS). WHILE RACE HAS BEEN RECOGNIZED AS A PIVOTAL SDOH IN APOS IN SLE, THERE IS A DEARTH OF DATA REGARDING THE INFLUENCE OF OTHER SDOH. THE OBJECTIVE OF THIS MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD IS TO DETERMINE THE CONTRIBUTION OF SDOH TO THE RISK OF APOS IN SLE. THE CENTRAL HYPOTHESIS IS THAT MULTIPLE DISCRETE SDOH CONTRIBUTE TO RISK OF APOS IN SLE PATIENTS. THE PRIMARY OUTCOME IS A COMBINATION OF FETAL MORBIDITY AND CDC-DEFINED MATERNAL MORBIDITY, AND THE SECONDARY OUTCOME IS A COMBINATION OF IN-HOSPITAL MATERNAL AND FETAL MORTALITY. WITH THE CANDIDATE’S EXPERIENCE IN HEALTH DISPARITIES RESEARCH AND HER MENTORING TEAM’S EXPERTISE IN SLE, QUALITATIVE RESEARCH AND MACHINE LEARNING, THE CANDIDATE WILL TEST THE HYPOTHESES WITH THE FOLLOWING AIMS: 1) TO QUANTIFY THE ASSOCIATIONS AND INTERACTIONS OF RACE AND INCOME WITH APOS IN PATIENTS WITH SLE; 2) TO IDENTIFY IMPORTANT NEIGHBORHOOD-LEVEL SDOH ASSOCIATED WITH APOS IN PATIENTS WITH SLE; AND 3) TO DETERMINE THE ABILITY OF INDIVIDUAL-LEVEL SDOH IN PREDICTING APOS IN PATIENTS WITH SLE. THE CANDIDATE WILL USE US NATIONWIDE DATA (~51,000 SLE PREGNANCIES) AND MACHINE LEARNING IN DATA FROM FIVE DISTINCT AND GEOGRAPHICALLY DIVERSE US STATES TO DETERMINE THE ASSOCIATION BETWEEN RACE AND NEIGHBORHOOD-LEVEL INCOME, AS WELL AS UNDERSTAND THE IMPACT OF OTHER NEIGHBORHOOD-LEVEL SDOH ON APOS IN PATIENTS WITH SLE. FURTHER, SHE WILL COLLECT BOTH PROSPECTIVE INDIVIDUAL-LEVEL SDOH DATA AT TWO NEW YORK CENTERS AND PERFORM QUALITATIVE INTERVIEWS WITH STAKEHOLDERS (RECENTLY PREGNANT PATIENTS WITH SLE, RHEUMATOLOGISTS, HIGH-RISK OBSTETRICIANS, AND SOCIAL WORKERS) TO CONTEXTUALIZE THE RESULTS AND TO ELICIT UNMEASURED SDOH. THROUGH THE STRATEGIC UTILIZATION OF MULTI-DIMENSIONAL DATA, AT THE END OF THIS PROJECT, DR. BELLA MEHTA (AWARDEE) WILL HAVE IDENTIFIED THE MOST MEANINGFUL SDOH THAT CONTRIBUTE TO APO RISK IN SLE BOTH AT AN INDIVIDUAL- AND COMMUNITY-LEVEL. OVER THE COURSE OF THIS MENTORED RESEARCH CAREER DEVELOPMENT AWARD, DR. MEHTA WILL OBTAIN ADVANCED TRAINING IN THE APPLICATION OF ESTABLISHED AND INNOVATIVE METHODS FOR MACHINE LEARNING, ACQUIRE A BROAD UNDERSTANDING OF THE CONCEPTS AND METHODS OF QUALITATIVE RESEARCH, AND DEVELOP PROFICIENCY IN ASSESSMENT OF REPRODUCTIVE HEALTH POLICIES AND PROGRAMS. DATA AND SKILLS FROM THIS STUDY WILL PROVIDE THE FOUNDATION FOR AN R01 TO DISENTANGLE THE ROLE OF DIFFERENT SDOH IN SLE PREGNANCY OUTCOMES AND DEVELOP A ROBUST RISK PREDICTION TOOL IN LARGE SLE COHORTS AND OTHER RHEUMATIC CONDITIONS. THUS, PATIENTS WHO NEED INTERVENTION CAN BE IDENTIFIED EARLY, AND FUTURE STRATEGIES AND POLICIES CAN BE DEVELOPED AND IMPLEMENTED TO REDUCE HEALTH DISPARITIES AND IMPROVE OUTCOMES IN INDIVIDUAL PATIENTS.

MAGNETIC RESONANCE AND ULTRASOUND IMAGING AS BIOMARKERS FOR DETECTION AND MONITORING OF PARSONAGE-TURNER SYNDROME (PTS)

ENDOTHELIAL CELL S1PR1 SHAPES THE AUTOIMMUNE RESPONSE AND MAY ATTENUATE INJURY IN EXPERIMENTAL LUPUS NEPHRITIS.

CIRCULATING CELL FREE TUMOR DNA (CTDNA) IN PATIENTS WITH IMMUNE CHECKPOINT INHIBITOR ASSOCIATED INFLAMMATORY ARTHRITIS (ICI-IA): DEVELOPING A BIOMARKER TO ASSESS IMMUNOSUPPRESSIVE DRUG SAFETY - PROJECT SUMMARY IMMUNE CHECKPOINT INHIBITORS (ICI) ARE MONOCLONAL ANTIBODIES THAT BLOCK REGULATORS OF T CELL ACTIVATION, ACTIVATING ANTI-CANCER IMMUNITY AND GREATLY IMPROVING OVERALL SURVIVAL IN PATIENTS WITH ADVANCED CANCER. HOWEVER, ICI COMMONLY CAUSE IMMUNE RELATED ADVERSE EVENTS (IRAE), INCLUDING INFLAMMATORY ARTHRITIS (ICI-IA). IT IS ESTIMATED THAT AS MANY AS 14,000 ICI-TREATED PATIENTS WILL DEVELOP ICI-IA EACH YEAR. ICI-IA CAN I. BE DESTRUCTIVE TO THE JOINT, II. PERSIST FOR MONTHS TO YEARS, AND III. REQUIRE TREATMENT WITH GLUCOCORTICOIDS AND IMMUNOSUPPRESSIVE DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDS). HOWEVER, IMMUNOSUPPRESSION MAY WORSEN CANCER SURVIVAL IN THIS SETTING. IDENTIFYING THE SAFEST APPROACH TO ICI-IA MANAGEMENT (WITH REGARD TO TUMOR CONTROL) IS A CRITICAL UNMET NEED. HOWEVER, CANCER RECURRENCE IS MEASURED ON RADIOGRAPHIC IMAGING WHICH IS OFTEN PERFORMED MONTHS AFTER ICI-IA TREATMENT IS INITIATED AND THIS MAKES IT DIFFICULT TO DISENTANGLE WHICH MEDICATION OR INTERVENTION MAY HAVE BEEN RESPONSIBLE. IN THIS STUDY, WE USE MRD-EDGE, A NEW ULTRA- SENSITIVE APPROACH TO MEASURE CIRCULATING CELL FREE TUMOR DNA (CTDNA) AND IDENTIFY PATIENTS WITH CANCER RECURRENCE LONG BEFORE IT IS DEMONSTRATED ON STANDARD OF CARE RADIOGRAPHIC IMAGING. MRD-EDGE COUPLES WHOLE GENOME SEQUENCING WITH DEEP LEARNING APPROACHES TO PROVIDE A TUMOR FRACTION DETECTION SENSITIVITY AS LOW AS 10-5 AND ALLOW TRACKING OF CANCER CTDNA OVER TIME, EVEN IN PATIENTS WITH A LOW TUMOR BURDEN. EVEN MORE CRITICALLY, THIS APPROACH DOES NOT REQUIRE REFERENCE TO MATCHED TUMOR TISSUE. THIS IS IMPORTANT BECAUSE SIMULTANEOUS TUMOR SAMPLING IS IMPRACTICAL IN MOST CLINICAL SETTINGS (E.G., RHEUMATOLOGY CLINIC). THIS STUDY TAKES ADVANTAGE OF PLASMA SAMPLES FROM PATIENTS ENROLLED IN ONE OF TWO LARGE PROSPECTIVE ICI-IA REGISTRIES, THE HOSPITAL FOR SPECIAL SURGERY RHEUMATIC IRAE REGISTRY (2018-2022), AND THE MULTICENTER RHEUMATOLOGY ADVERSE EVENTS DUE TO IMMUNOTHERAPY OBSERVATIONAL STUDY (RADIOS) REGISTRY (FIRST ENROLLMENT 1/2023). IN AIM 1, WE MEASURE CTDNA LEVELS IN PATIENTS WITH MELANOMA OR NON-SMALL CELL LUNG CANCER (NSCLC) AT THEIR FIRST VISIT FOR ICI-IA TO QUANTIFY THE ASSOCIATION BETWEEN CTDNA AND SUBSEQUENT CANCER PROGRESSION. IN AIM 2, WE MEASURE CHANGES IN CTDNA FROM BASELINE TO WEEKS 4, 8 AND 12 AFTER INSTITUTION OF GLUCOCORTICOIDS IN ICI-IA PATIENTS, TO ASSESS THE SENSITIVITY OF THIS BIOMARKER TO THE EFFECTS OF IMMUNOSUPPRESSION, AND THE KINETICS OF CHANGE. OUR OVERARCHING HYPOTHESIS IS THAT CTDNA CAN BE DETECTED IN PATIENTS WITH ICI-IA LONG BEFORE CANCER PROGRESSION IS DEMONSTRATED ON IMAGING, AND THAT ANY RISE IN CTDNA WILL BE DETECTABLE WITHIN 4 WEEKS OF INITIATING GLUCOCORTICOIDS. THIS STUDY WILL PROVIDE PRELIMINARY DATA AND OPTIMAL PLASMA SAMPLING TIMES FOR A FUTURE INTERVENTIONAL STUDY (E.G., COMPARING UP-FRONT GLUCOCORTICOIDS TO UP-FRONT IL6R INHIBITION FOR HIGH-GRADE IRAE). IF EFFECT SIZES ARE SMALL, WE WILL PLAN A MUCH LARGER MULTICENTER OBSERVATIONAL STUDY POWERED TO ASSESS CTDNA LEVELS BEFORE AND AFTER STEROID-SPARING IMMUNOSUPPRESSIVE AGENTS INCLUDING IL6 AND TNF INHIBITORS.

LEUKOCYTE ADHESION MOLECULES MODULATE INFLAMMATION OF CARTILAGE IN JOINT TRAUMA

IRHOM2, A NEW TARGET FOR TREATMENT OF TNF-ALPHA-DEPENDENT PATHOLOGIES

REGULATION OF OSTEOCLASTOGENESIS AND ARTHRITIC BONE RESORPTION BY RBP-J

NEGATIVE REGULATION OF OSTEOCLASTOGENESIS BY INFLAMMATORY SIGNALS

ASSESSING RISK FOR POOR OUTCOMES IN ANTIPHOSPHOLIPID SYNDROME - PROJECT SUMMARY/ABSTRACT BACKGROUND: THIS PROPOSAL IS DESIGNED FOR MEDHA BARBHAIYA, MD, MPH TO GROW TOWARDS BECOMING AN INDEPENDENT INVESTIGATOR FOCUSED ON DEVELOPING AND VALIDATING A NOVEL METHOD TO IDENTIFY ANTIPHOSPHOLIPID SYNDROME (APS) IN LARGE COHORTS, EVALUATING ITS UTILITY IN IDENTIFYING POOR APS OUTCOMES IN MULTI-CENTER EHR COHORTS, AND IDENTIFYING DISCRETE APS SUBPHENOTYPES BASED ON LONGITUDINAL AUTOANTIBODY AND BIOMARKER DATA. CURRENTLY, THERE IS NO ACCURATE WAY TO IDENTIFY APS PATIENTS IN LARGE COHORTS, LIMITING UNDERSTANDING OF THE ROLE OF MODIFIABLE RISK FACTORS FOR OUTCOMES ACROSS SOCIODEMOGRAPHIC GROUPS. ADDITIONALLY, WHILE CERTAIN APL PROFILES MAY CONFER INCREASED THROMBOTIC RISKS, THE EXTENT TO WHICH NOVEL BIOMARKERS PREDICT CLINICAL OUTCOMES IS UNKNOWN. PRELIMINARY DATA: FOR AIM 1, WE HAVE BEGUN ASSESSING THE FEASIBILITY OF DEVELOPING THE FIRST ALGORITHMS FOR APS IDENTIFICATION USING STRUCTURED EHR DATA. IN THE HOSPITAL FOR SPECIAL SURGERY (HSS) ELECTRONIC HEALTH RECORD (EHR), WE HAVE APPLIED A BROAD SCREENING FILTER TO IDENTIFY ALL POTENTIAL APS PATIENTS (N=1,318 POTENTIAL ADULT APS CASES WITH ≥1 APS ICD-10-CM [D68.61] CODE SINCE JANUARY 1, 2016). UNDER THE GUIDANCE OF HER MENTORS, DR. BARBHAIYA WILL RANDOMLY SELECT 200 OF THESE SUBJECTS AS A ‘TRAINING SET’ FOR CHART REVIEW TO IDENTIFY THEIR TRUE CASE STATUS. FOR AIM 2, WE HAVE RECENTLY DESCRIPTIVELY EVALUATED THE APS ACTION REGISTRY, THE LARGEST AND LONGEST PROSPECTIVE REGISTRY OF PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES (APL) TO STUDY ASSOCIATIONS BETWEEN APL PROFILE AND CLINICAL EVENTS. WE WILL NOW APPLY BIOINFORMATICS APPROACHES TO EVALUATE THE ASSOCIATION OF NOVEL APS BIOMARKERS WITH APL PROFILE AND CLINICAL OUTCOMES IN THIS ONGOING PROSPECTIVE REGISTRY. METHODS: AS PART OF THIS K23 AWARD, WE WILL DEVELOP ALGORITHMS USING STRUCTURED AND UNSTRUCTURED DATA USING NATURAL LANGUAGE PROCESSING AND MACHINE LEARNING APPROACHES. WE SEPARATELY PLAN TO SUBPHENOTYPE ANTIPHOSPHOLIPID ANTIBODY (APL) PATIENTS IN THE ONGOING PROSPECTIVE APS ACTION REGISTRY USING NOVEL BIOMARKERS AND APL PROFILE. WE WILL USE CLASSICAL CLUSTERING METHODS AS WELL AS UNSUPERVISED MACHINE LEARNING TO CROSS-SECTIONALLY AND LONGITUDINALLY EVALUATE FOR AN ASSOCIATION WITH APS CLINICAL OUTCOMES AFTER ADJUSTING FOR DEMOGRAPHIC AND OTHER CLINICAL FACTORS. CAREER DEVELOPMENT: THIS PROPOSAL EMPLOYS NOVEL METHODS TO ADDRESS GAPS IN KNOWLEDGE RELATED TO APS EPIDEMIOLOGY. DR. BARBHAIYA IS AN ASSISTANT PROFESSOR IN MEDICINE AND POPULATION HEALTH SCIENCES AT WEILL CORNELL MEDICINE AND AN ASSISTANT ATTENDING AT HOSPITAL FOR SPECIAL SURGERY WITH ACCESS TO OUTSTANDING SERVICES AND ENVIRONMENT AT THESE INSTITUTIONS. SHE HAS ASSEMBLED A STRONG MULTI-DISCIPLINARY MENTORING TEAM AND WILL BE ABLE TO COMPLETE FORMAL TRAINING IN BIOINFORMATICS, BIOMARKER ASSAY INTERPRETATION, IMMUNOLOGY, LEADERSHIP AND MENTORING SKILLS. THIS PROJECT HAS THE POTENTIAL TO LEAD TO FUTURE GRANTS AND STUDIES, AND WILL POSITION DR. BARBHAIYA TO ACHIEVE HER OBJECTIVE TO BECOME AN R01-FUNDED INDEPENDENT INVESTIGATOR FOCUSED ON IMPROVING APS OUTCOMES.

REGIONALIZATION OF ELECTIVE TOTAL JOINT REPLACEMENT

PROTEOGLYCAN REGULATION OF GROWTH PLATE CARTILAGE CALCIFICATION

EFFECTS OF BONE TISSUE MINERAL AND MATRIX PROPERTIES ON FRACTURE INCIDENCE

COMPARING PATIENTS' AND SURGEONS' EXPECTATIONS OF LUMBAR SPINE SURGERY

FLUORESCENT STEREOMICROSCOPE

LUPUS 2016

15TH INTERNATIONAL CONGRESS ON ANTIPHOSPHOLIPID ANTIBODIES

SHF: LARGE: COLLABORATIVE RESEARCH: MOLECULAR COMPUTING FOR THE REAL WORLD