University Health Network

PRINCESS MARGARET PHASE I CONSORIUM (PMP1C)

DURABILITY OF HBV DNA SUPPRESSION IN CIRRHOTICS AFTER STOPPING THERAPY

MECHANISMS OF VIRAL PERSISTENCE

CELL POLARITY REGULATION DURING BREAST CANCER PROGRESSION: NOVEL PATHWAYS FOR DIAGNOSIS AND TREATMENT

GENERATION OF FUNCTIONAL BETA CELLS FROM STEM AND PROGENITOR CELLS

DEVELOPMENT OF A NEXT-GENERATION PSD95 INHIBITOR FOR THE TREATMENT OF ACUTE ISCHE

ESTABLISHING REFERENCE VALUES AND CLINICAL DECISION POINTS FOR QUANTITATIVE VIDEOFLUOROSCOPIC MEASURES OF SWALLOWING - PROJECT SUMMARY/ABSTRACT DYSPHAGIA (SWALLOWING IMPAIRMENT) IS A SERIOUS HEALTH CONDITION SEEN IN MANY AGE-RELATED DISEASE AND INJURY PROCESSES. ALTHOUGH VIDEOFLUOROSCOPY (VF) IS AN INTERNATIONAL “GOLD STANDARD” DYSPHAGIA DIAGNOSTIC EXAM, THERE IS A PAUCITY OF AVAILABLE NORMATIVE PHYSIOLOGIC VF REFERENCE VALUES IN HEALTHY ADULTS ACROSS THE AGE SPAN TO GUIDE INTERPRETATION OF THIS EXAMINATION. THIS FUNDAMENTAL GAP IN KNOWLEDGE CONTRIBUTES TO POOR AGREEMENT IN THE IDENTIFICATION OF SWALLOWING IMPAIRMENT AND ITS UNDERLYING MECHANISMS. TO ENABLE BETTER DYSPHAGIA DIAGNOSTICS, THERE IS A CRITICAL NEED TO ESTABLISH REFERENCE VALUES FOR VF SWALLOWING MEASURES ACROSS THE HEALTHY AGE SPAN. IN OUR PREVIOUS R01 (DC011020), WE DEVELOPED A RIGOROUS METHOD FOR MEASURING SWALLOWING PHYSIOLOGY FROM VF: THE ANALYSIS OF SWALLOWING PHYSIOLOGY: EVENTS, KINEMATICS AND TIMING (ASPEKT METHOD). WE PUBLISHED INITIAL ASPEKT REFERENCE VALUES FROM 40 YOUNG HEALTHY ADULTS (<60 YEARS) AND PERFORMED PRELIMINARY ANALYSES TO COMPARE DATA FROM HEALTHY OLDER ADULTS AND SMALL COHORTS OF ADULTS WITH DYSPHAGIA TO THESE REFERENCE DATA. THROUGH THIS RENEWAL APPLICATION, WE WILL VALIDATE THE ASPEKT METHOD HEALTHY REFERENCE VALUES FOR SWALLOWING ACROSS THE ADULT LIFE SPAN, DEMONSTRATE SCALABILITY OF THE ASPEKT METHOD ACROSS COMMONLY USED VARIATIONS IN CLINICAL VF TESTING PROTOCOLS, AND PROFILE SWALLOWING PATHOPHYSIOLOGY IN CLINICAL GROUPS WHERE DYSPHAGIA IS A CAUSE OF MORBIDITY TO IDENTIFY CLINICAL DECISION POINTS THAT CAN BE USED FOR DIAGNOSIS AND OUTCOME MEASUREMENT. OUR VISION IS THAT THE ASPEKT METHOD WILL ENABLE CLINICIANS TO COMPARE PATIENT MEASURES TO HEALTHY REFERENCE VALUES, FACILITATING QUANTIFICATION AND EVIDENCE- BASED INTERPRETATION OF THE PRESENCE, NATURE AND SEVERITY OF SWALLOWING IMPAIRMENT. ULTIMATELY, WE SEEK TO GENERATE DATA THAT WILL SHIFT SUBJECTIVE DYSPHAGIA DIAGNOSTIC PRACTICES TOWARD A QUANTITATIVE, EVIDENCE-BASED DIAGNOSTIC FRAMEWORK THAT WILL IMPROVE RESOURCE UTILIZATION, TREATMENT PLANNING AND PATIENT OUTCOMES.

PRINCESS MARGARET HOSPITAL PHASE I CONSORTIUM

DETERMINANTS OF BREAST TISSUE COMPOSITION IN YOUNG WOMEN

TONGUE-PRESSURE TIMING FOR LIQUID FLOW DETECTION AND CONTROL IN SWALLOWING

HUMAN SHP2 (PTPN11) MUTATIONS AND CARDIAC VALVE DEVELOPMENT

SIGNAL TRANSDUCTION BY NON-TRANSMEMBRANE PTPS

ESTABLISHING THE CLINICAL UTILITY OF CELL-FREE TUMOR DNA METHYLATION PROFILING AS A RELIABLE LIQUID BIOPSY APPROACH IN BRAIN TUMORS - PROJECT SUMMARY TUMORS OF THE CENTRAL NERVOUS SYSTEM (CNS) ARE THE MOST FATAL MALIGNANCIES. DETERMINING THE OPTIMAL TREATMENT FOR PATIENTS RELIES ON ACCURATE DIAGNOSES, WHICH AT PRESENT IS ONLY ACHIEVABLE BY HISTOPATHOLOGICAL ANALYSES OF THE TISSUE OBTAINED BY INVASIVE BRAIN SURGERY. OPERATIONS IN THE BRAIN INSTILL TREMENDOUS ANXIETY IN PATIENTS AND POSE A SIGNIFICANT RISK FOR NEUROLOGICAL MORBIDITY AND EVEN MORTALITY. IN ADDITION, ACCURATE LONGITUDINAL MONITORING OF RESPONSE TO TREATMENT, AND DISTINGUISHING RECURRENCE FROM TREATMENT-RELATED EFFECTS (PSEUDOPROGRESSION), RELIES ON LIMITED INFORMATION OBTAINED ON RADIOLOGIC IMAGING AS THE OPTION TO INVASIVELY OBTAIN TISSUE LONGITUDINALLY OVER THE COURSE OF DISEASE IS PROHIBITIVE DUE TO THE MORBIDITY OF REPEAT PROCEDURES. GIVEN THESE LIMITATIONS, THERE HAS BEEN SIGNIFICANT INTEREST IN IDENTIFYING NON-INVASIVE OR “LIQUID” BIOMARKERS FOR THE DIAGNOSIS OF CNS TUMORS. MOST GROUPS HAVE LOOKED AT MUTATIONS IN CIRCULATING CELL-FREE TUMOR DNA IN THE PLASMA OR CEREBROSPINAL FLUID. UNFORTUNATELY, CNS TUMORS USUALLY DO NOT RELEASE ENOUGH DNA INTO THE SYSTEMIC CIRCULATION FOR SUCH AN APPROACH TO BE RELIABLE ON A PROSPECTIVE CLINICAL BASIS. FURTHERMORE, SEARCHING FOR SINGLE MUTATIONS DOES NOT ALLOW FOR THE DISCRIMINATION OF THE MANY DIFFERENT TYPES OF BRAIN TUMORS INCLUDED IN A DIFFERENTIAL DIAGNOSIS. INSTEAD OF FOCUSING ON MUTATIONS, WE FOCUSED ON DNA METHYLATION ALTERATIONS THAT ARE HIGHLY ABUNDANT AND CANCER SPECIFIC. WE DEVELOPED, OPTIMIZED, AND VALIDATED A NOVEL APPROACH TERMED CELL-FREE METHYLATED DNA IMMUNO-PRECIPITATION AND SEQUENCING (CFMEDIP-SEQ) THAT INVOLVES ISOLATING AND ENRICHING FOR METHYLATED FRAGMENTS OF TUMOR CELL-FREE DNA USING A METHYLATION-SPECIFIC ANTIBODY AND THEN SEQUENCING. PUBLISHED DATA FROM OUR GROUP PROVIDES PROOF-OF-PRINCIPLE THAT PLASMA CFMEDIP-SEQ CAN RELIABLY AND ACCURATELY DIAGNOSE TUMORS THROUGHOUT THE BODY, INCLUDING THOSE IN THE CNS. BASED ON THESE DATA, WE HYPOTHESIZE THAT METHYLATION PROFILING OF CIRCULATING DNA, VIA CFMEDIP-SEQ, IDENTIFIES RELIABLE BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, AND MONITORING OF CNS TUMORS NON-INVASIVELY. WE WILL BUILD UPON OUR EXISTING DATA TO USE CFMEDIP-SEQ AS A NOVEL TECHNIQUE TO ESTABLISH AND VALIDATE A COMPREHENSIVE, NON-INVASIVE CNS TUMOR CLASSIFIER (AIM 1); BUILD AN ACCURATE PREDICTIVE MODEL FOR THE NON-INVASIVE PROGNOSTICATION OF MENINGIOMAS (AIM 2); IDENTIFY PLASMA BIOMARKERS OF RESPONSE TO TREATMENT, RECURRENCE, AND MALIGNANT TRANSFORMATION IN GLIOMAS (AIM 3); AND IDENTIFY METHYLATION AND PLASMA BIOMARKERS OF BRAIN METASTASES DEVELOPMENT FROM SYSTEMIC CANCERS (AIM 4). SUCCESS IN THIS PROPOSAL WILL GENUINELY HELP SHAPE A MUCH-NEEDED PARADIGM-SHIFT IN THE FIELD OF NEURO-ONCOLOGY BY ESTABLISHING CFMEDIP-SEQ AS A RELIABLE LIQUID BIOMARKER FOR THE NON-INVASIVE DIAGNOSIS, PROGNOSTICATION, AND MONITORING OF PATIENTS WITH PRIMARY AND METASTATIC CNS TUMORS.

MECHANISTIC INVESTIGATIONS OF MICROBIOME-DRIVEN ARYL HYDROCARBON RECEPTOR ACTIVITY AND MACROPHAGE FUNCTION IN PANCREATIC CANCER. - PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS ONE OF THE LEADING CAUSES OF CANCER- RELATED DEATH. THIS IS ATTRIBUTABLE TO THE ASYMPTOMATIC EARLY STAGES OF DISEASE, THE FIBROTIC NATURE OF THE TUMOR, AND THE LACK OF RESPONSE TO SURGERY, CHEMO- AND IMMUNOTHERAPIES. THE LACK OF RESPONSE TO IMMUNOTHERAPY IS DESPITE THE FACT THAT PANCREATIC CANCER EXHIBITS A SIGNIFICANT IMMUNE INFILTRATE. RELATIVELY LITTLE IS UNDERSTOOD ABOUT THE IMMUNE LANDSCAPE IN PDAC, BUT IT IS CLEAR THAT SUPPRESSIVE POPULATIONS OF MACROPHAGES LIKELY PLAY A KEY ROLE IN SHAPING THE TUMOR MICROENVIRONMENT AND TARGETING THEM COULD IMPACT RESPONSES TO THERAPY. LIKEWISE, ALTERED MICROBIOME ACTIVITY HAS BEEN LINKED TO PANCREATIC CANCER PROGRESSION, RESISTANCE TO IMMUNE THERAPY, AND SURVIVAL TIMES IN PATIENTS. RECENTLY WE DESCRIBED A CRITICAL ROLE FOR THE ARYL HYDROCARBON RECEPTOR (AHR) AS A DRIVER OF MACROPHAGE SUPPRESSIVE FUNCTION. SINCE AHR IS AN IMPORTANT SENSOR OF MICROBIAL METABOLITES, WE SURMISED THAT THE MICROBIOME MAY DRIVE TUMOR MACROPHAGE FUNCTION VIA THE METABOLIC PRODUCTS PRODUCED BY THE FLORA; WHILE BLOCKING AHR ACTIVITY WOULD CAUSE THE TUMOR MICROENVIRONMENT TO BECOME “HOT” ENHANCING RESPONSES TO STANDARD-OF-CARE CHEMOTHERAPY AND IMMUNOTHERAPY. THE GOAL OF THIS PROPOSAL IS TO INVESTIGATE HOW THE MICROBIOME ALTERS IMMUNITY IN THE TUMOR MICROENVIRONMENT. TO ACHIEVE THIS GOAL, WE HAVE DEVELOPED AN ORTHOTOPIC MOUSE MODEL OF PDAC. OUR PRELIMINARY DATA DEMONSTRATE THAT AHR IS CRITICAL FOR TUMOR GROWTH AND SPECIFIC METABOLITES PRODUCED BY LACTOBACILLUS SPECIES DRIVE MACROPHAGE SUPPRESSIVE FUNCTION AND SUPPRESS T CELL INFLAMMATORY MATURATION. IN THE CURRENT PROPOSAL, WE WILL MECHANISTICALLY INVESTIGATE HOW THE MODULATION OF MACROPHAGE FUNCTION BY AHR OCCURS IN THE TUMOR MICROENVIRONMENT. WE WILL THEN EXAMINE THE PREDICTION THAT BLOCKING AHR WILL IMPROVE TUMOR RESPONSES TO GEMCITABINE AND CHECKPOINT INHIBITOR THERAPY, AND FINALLY WE WILL TEST PREDICTIONS GENERATED IN THE MOUSE MODELS IN HUMAN MACROPHAGES AND EXAMINE THE CORRELATION BETWEEN THE MICROBIOME, AHR ACTIVITY, AND SURVIVAL IN PDAC PATIENTS. THE EXPERIMENTS OUTLINED IN THIS PROPOSAL WILL ESTABLISH IMPORTANT BIOLOGIC PRINCIPLES AND PROVIDE A NEW MECHANISTIC LINK BETWEEN MICROBIOME:TUMOR INTERACTIONS THAT FOSTERS GROWTH AND METASTASIS. ULTIMATELY, THE MECHANISMS AND PARADIGMS WE REVEAL HAVE THE POTENTIAL TO LEAD TO NEW STRATEGIES TO TREAT PDAC AND SIGNIFICANTLY IMPACT CLINICAL OUTCOMES FOR THIS TERRIBLE DISEASE.

IMMUNOENGINEERING OF DONOR LUNGS TO OPTIMIZE LONG-TERM GRAFT FUNCTION - PROJECT SUMMARY LUNG TRANSPLANTATION IS THE ONLY TREATMENT OPTION FOR PATIENTS WITH END-STAGE LUNG DISEASE. HOWEVER, TRANSPLANT OUTCOMES ARE SIGNIFICANTLY LIMITED BY THE DEVELOPMENT OF PRIMARY GRAFT DYSFUNCTION (PGD), CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD), AND COMPLETE ORGAN REJECTION. WITH INCREASING LUNG TRANSPLANT ACTIVITY AROUND THE WORLD, NEW ADVANCEMENTS ARE URGENTLY NEEDED TO IMPROVE PATIENT SURVIVAL AND QUALITY OF LIFE. AT UNIVERSITY HEALTH NETWORK (UHN), OUR TEAM PIONEERED THE TORONTO EX VIVO LUNG PERFUSION (EVLP) SYSTEM—A BREAKTHROUGH TECHNOLOGY WHEREBY DONOR LUNGS ARE PRESERVED IN A FUNCTIONAL PHYSIOLOGICAL STATE AT 37°C AND PROVIDED OXYGEN, NUTRIENTS, AND OTHER CRITICAL RESOURCES PRIOR TO TRANSPLANTATION. THIS ENABLES DONOR LUNGS TO “BREATHE” OUTSIDE OF THE BODY FOR UP TO 12 HOURS. USING EVLP, TRANSPLANT TEAMS CAN MORE OBJECTIVELY ASSESS MARGINAL DONOR LUNGS AND APPLY NOVEL REPAIR THERAPIES. TO THIS END, OUR PROJECT WILL LEVERAGE EVLP TO DEVELOP NOVEL SOMATIC CELL GENE EDITING (SCGE) THERAPEUTIC STRATEGIES THAT CAN BE APPLIED TO FURTHER ENHANCE DONOR LUNGS. IN PRELIMINARY RESEARCH, WE HAVE SHOWN THAT: 1) UPREGULATION OF AN ANTI-INFLAMMATORY CYTOKINE CALLED INTERLEUKIN (IL)-10 IMPROVES LUNG QUALITY AND POST- TRANSPLANT OUTCOMES; AND 2) RECIPIENT REGULATORY T CELLS (TREGS) THAT ARE RESISTANT TO TACROLIMUS (TAC) IMPROVE THE REGULATORY MICROENVIRONMENT IN THE TRANSPLANTED ORGAN. OUR HYPOTHESIS IS THAT APPLYING SCGE TECHNIQUES DURING EVLP WILL ENHANCE IL-10 GENE AND TREG CELL THERAPIES, WHICH WILL IMMUNOMODULATE THE DONOR ORGAN AND LESSEN THE RISK OF TRANSPLANT REJECTION. IN AIM 1, WE WILL ENGINEER NEW CRISPR EDITING TECHNOLOGIES FOR USE DURING EVLP AND ASSESS THE FEASIBILITY AND THERAPEUTIC POTENTIAL OF THIS APPROACH USING PRE-CLINICAL IN VIVO MODELS. IN AIM 2, WE WILL CONFER TAC RESISTANCE IN TREG CELLS USING BASE EDITING AND ASSESS TREG EFFICACY IN VIVO USING A HUMAN SKIN XENOGRAFT MODEL. IN AIM 3, WE WILL CONDUCT PROOF-OF-CONCEPT TRANSLATIONAL STUDIES AND ASSESS THE EFFICACY OF OUR COMBINED THERAPIES USING CLINICALLY DECLINED HUMAN LUNGS ON EVLP, REPRESENTING THE CLOSEST APPROXIMATION PRIOR TO CLINICAL APPLICATION. IN OUR CONTINUED LEADERSHIP OF THE FIELD, WE WILL ENHANCE OUR STRATEGIC COLLABORATION WITH MASSACHUSETTS GENERAL HOSPITAL TO EXPLORE THIS MULTIDISCIPLINARY APPROACH TO LONG-TERM TRANSPLANT TOLERANCE. OUR PROJECT GOAL TO COMBINE SCGE AND EVLP STRATEGIES WILL ENABLE A GRANDER PURSUIT OF OUR LONG-TERM AMBITION: TO ‘DESIGN’ BETTER LUNGS THAT WILL LAST A LIFETIME IN THE TRANSPLANT RECIPIENT. ACHIEVEMENT OF OUR PROPOSED OBJECTIVES WILL RESULT IN NOVEL CLINICAL APPLICATIONS AND A PARADIGM SHIFT IN HOW WE TREAT LUNG TRANSPLANT RECIPIENTS—AWAY FROM A LIFE OF IMMUNOSUPPRESSIVE MEDICATIONS AND TOWARDS SELF-SUSTAINING AND LONG-TERM GRAFT TOLERANCE.

CATCH: CREATING ACCESS TO TRANSPLANT FOR CANDIDATES WHO ARE HIGH RISK - PROJECT SUMMARY TODAY, LUNG TRANSPLANTATION FOR PATIENTS WITH END-STAGE LUNG DISEASE HAS BECOME INCREASINGLY STANDARDIZED AROUND THE WORLD, THANKS TO DECADES OF INTERNATIONAL COLLABORATION AND PARTNERSHIP. AS A RESULT, MORE PATIENTS CAN RECEIVE A LIFE-SAVING PROCEDURE AND BENEFIT FROM VASTLY IMPROVED SURVIVAL AND QUALITY OF LIFE. HOWEVER, ACCESS TO LUNG TRANSPLANT REMAINS PARTICULARLY VARIABLE FOR THREE CATEGORIES OF HIGH-RISK PATIENTS: 1) HIGHLY SENSITIZED PATIENTS; 2) PATIENTS REQUIRING EXTRACORPOREAL MEMBRANE OXYGENATION SUPPORT AS A BRIDGE TO TRANSPLANT (ECMO-BTT); AND 3) PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS, INCLUDING THOSE WITH COVID-19-ASSOCIATED ARDS). BECAUSE THESE PATIENTS ARE AT HIGH-RISK FOR COMPLICATIONS AND HISTORICALLY UNDERSTUDIED, THERE ARE NO CLEAR GUIDELINES FOR THEIR TREATMENT. AS A RESULT, THEY ARE UNIQUELY DISADVANTAGED: RECEIVING A TRANSPLANT LARGELY DEPENDS ON THEIR PROGRAM’S WILLINGNESS TO ACCEPT THE RISK OF TRANSPLANT WITHOUT SUFFICIENT DATA TO INFORM HOW IT CAN BE OPTIMALLY AND SAFELY PERFORMED. PROGRAMS, THEREFORE, DIFFER IN THE SELECTION AND MANAGEMENT OF THESE PATIENTS, CREATING SIGNIFICANT DISPARITIES AND VARIATION IN CARE ACROSS CENTERS, ULTIMATELY TO THE DETRIMENT OF THE TRANSPLANT CANDIDATE. WITH SUPPORT FROM THE NIH LUNG TRANSPLANT CONSORTIUM, WE PROPOSE THE FORMATION OF CATCH: CREATING ACCESS TO TRANSPLANT FOR CANDIDATES WHO ARE HIGH RISK, WITH THE GOAL TO IMPROVE ACCESS AND OUTCOMES FOR THESE PATIENTS IN NEED. THE FOUR LUNG TRANSPLANT PROGRAMS THAT COMPRISE CATCH—UNIVERSITY HEALTH NETWORK, UNIVERSITY OF FLORIDA, COLUMBIA UNIVERSITY, AND BRIGHAM AND WOMEN’S HOSPITAL—COLLECTIVELY PERFORM OVER 400 LUNG TRANSPLANTATIONS PER YEAR, AND EACH HAVE EXTENSIVE BUT DIFFERING EXPERIENCE IN MANAGING THESE PATIENTS. OUR CATCH STUDY HYPOTHESIS IS THAT OUR INDIVIDUAL MANAGEMENT STRATEGIES SIGNIFICANTLY IMPACT HIGH-RISK CANDIDATES’ LIKELIHOOD OF RECEIVING A TRANSPLANT AND THEIR POST-TRANSPLANT OUTCOMES. THROUGH PROSPECTIVE COHORT STUDIES, WE AIM TO DEVISE AN OPTIMAL AND UNITED STRATEGY THAT ADDRESSES THE SPECIFIC UNMET NEEDS OF THESE HIGH RISK PATIENTS. OUR TEAM HAS BEEN CAREFULLY ASSEMBLED BASED ON SCIENTIFIC MERIT AND STRATEGIC COLLABORATION, REPRESENTING MULTIDISCIPLINARY STRENGTHS IN THORACIC SURGERY AND LUNG TRANSPLANT PULMONOLOGY THAT WILL COMPLEMENT OUR RECOGNIZED RESEARCH LEADERSHIP. WE HAVE EXTENSIVE EXPERIENCE IN SUCCESSFUL PROJECT MANAGEMENT FOR LARGE MULTI-SITE PROJECTS, AND OUR EXPERTISE IN DEVELOPING STANDARDIZED PROTOCOLS AND CONSENSUS DOCUMENTS WILL HELP TO MAXIMIZE THE POTENTIAL ACROSS ALL TRANSPLANT CENTERS. ULTIMATELY, AS KEY OPINION LEADERS IN A FIELD THAT ACTIVELY LOOKS TO US FOR GUIDANCE, OUR CATCH PROJECT OUTCOMES ARE STRONGLY POSITIONED TO HAVE AN IMMEDIATE TRANSFORMATIVE IMPACT BY STANDARDIZING THE FIELD AND ENSURING THAT EVERY PATIENT IN NEED OF A LUNG TRANSPLANT CAN RECEIVE ONE.

THE SURVEILLANCE RECEPTOR TRPM2: A NOVEL THERAPEUTIC TARGET FOR RETT SYNDROME?

DEFINING THE IMPACT OF DOLUTEGRAVIR ON THE MATERNAL METABOLIC ENVIRONMENT AND ITS IMPLICATIONS ON RISK OF CONGENITAL ANOMALIES.

UNDERSTANDING THE MOLECULAR MECHANISM OF A PROTEIN-RECYCLING COMPLEX IN SMALL CELL LUNG CANCER TREATMENT RESISTANCE.

UNIVERSITY HEALTH NETWORK'S APPLICATION TO JOIN THE A2ALL CONSORTIUM

COMPREHENSIVE EVALUATION OF IMMUNE FUNCTION IN PATIENTS RECEIVING MULTIMODAL THERAPY FOR HIGH-RISK NEUROBLASTOMA

ENDODERM INDUCTION AND PANCREATIC SPECIFICATION FROM ES*

THE ROLE OF MARGINAL ZONE MACROPHAGES AND IMMUNO-METABOLISM IN TUMOR-DRIVEN MDSC DEVELOPMENT

MECHANISTIC RELATIONSHIPS BETWEEN IDO, GCN2, AND MTOR SIGNALS IN IMMUNITY TO APOPTOTIC CELLS

INHIBITING INTERACTION OF PNUTS WITH THE MYC FAMILY OF ONCOPROTEINS TO EFFECTIVELY TARGET BREAST CANCER

BREAST AND PROSTATE CANCER RISK SNPS REGULATE FOXA1 AND NUCLEAR RECEPTOR ACTIVITY

GENERATION OF HIGHLY AVID ANTI-TUMOR CTL FOR OPTIMAL ADOPTIVE IMMUNOTHERAPY

DEFINING THE ROLE OF THE RAS PATHWAY IN BRAIN ARTERIOVENOUS MALFORMATIONS

TARGETING MITOCHONDRIAL PROTEIN SYNTHESIS WITH TIGECYCLINE FOR THE TREATMENT OF L

TARGETING THE MEVALONATE PATHWAY AND ITS RESTORATIVE FEEDBACK LOOP IN BREAST CANCER

4/4-SUSTAINING REMISSION OF PSYCHOTIC DEPRESSION

THERAPEUTIC TARGETING OF GENOMIC INSTABILITY IN TRIPLE NEGATIVE BREAST CANCER

ROLE OF GAB2 AND SHP2 IN HEMATOPOIETIC SIGNALLING

THE DMPFC AS A TARGET IN TREATMENT-RESISTANT BULIMIA NERVOSA AND ANOREXIA NERVOSA:INVESTIGATING TARGET ENGAGEMENT, DOSING, RELIABILITY AND DURATION OF EFFECT USING RTMS, FMRI,AND A SHAM CONTROLLED ARM

GENOMIC AND EPIGENOMIC CHARACTERIZATION OF NF1-RELATED SPECTRUM OF PERIPHERAL NERVE SHEATH TUMORS.

EWING-LIKE SARCOMA: TARGETING THE CIC-DUX4 ONCOGENE THROUGH EPIGENETIC REGULATORS

MODELING AND TARGETING METASTATIC DRIVERS IDENTIFIED IN SLEEPING BEAUTY SCREENS AND CODING FOR CYTOPLASMIC SIGNALING PROTEINS

INVESTIGATION OF CELL TYPES RESPONSIBLE FOR SEIZURE GENERATION IN A MODEL OF NEUROFIBROMATOSIS TYPE 1

OPTIMIZING EARLY-PHASE TRANSLATIONAL OVARIAN CANCER CLINICAL TRIALS WITH INTEGRATIVE COMPUTATIONAL BIOLOGY

IDENTIFYING NOVEL IMMUNE EVASION TUMOR IMMUNE NETWORKS AS TARGETS FOR CCRCC IMMUNOTHERAPY

DYNAMIC MULTI-ORGAN ANATOMICAL MODELS FOR HYPOFRACTIONATED RT DESIGN AND DELIVERY

HEMATOPOIETIC DEVELOPMENT FROM ES CELLS

USING ADMINISTRATIVE HEALTH DATA TO IDENTIFY PATIENTS WITH NF1 IN ONTARIO, CANADA, AND TO ASSESS PREVALENCE, MORTALITY, AND HEALTH CARE UTILIZATION PATTERNS.

FUNCTIONAL ASSESMENT AND CHARACTERIZATION OF MDV3100-RESISTANT CALL LINES

JAK/STAT ACTIVATION DRIVES CIC-REARRANGED SARCOMA

PATHWAYS INFLUENCING LEFT VENTRICULAR HYPERTROPHY IN HEMODIALYSIS PATIENTS

HMGB1 AND ITS ISOFORMS AS BIOMARKERS FOR MINERAL FIBER EXPOSURE AND MM DETECTION

THE ROLE OF KIF14 IN OVARIAN CANCER

TARGETING THE MEVALONATE PATHWAY AND ITS RESTORATIVE FEEDBACK LOOP IN BREAST CANCER

OF THE RB AND P53 KTUMOR SUPPRESSOR PATHWAYS IN MAMMARY TUMORIGENESIS

PROGRESSION FROM DEVELOPING RETINA TO RETINOBLASTOMA

FAMILY THERAPY AND FLUOXETINE IN THE TREATMENT OF ADOLESCENTS

THALASSEMIA CLINICAL RESEARCH NETWORK, CANADA

RESTORING ANTIBODY EFFECTOR FUNCTION DURING PERSISTENT VIRUS INFECTION

SELECTIVE LETHALITY BY TARGETING GENE ESSENTIALITY IN RESISTANT OVARIAN CANCER THROUGH DYNAMIC MONITORING OF THE ACTIVE KINOME

LINEAGE TRACING IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS AND PLEXIFORM NEUROFIBROMAS TO ASSESS TUMORAL HETEROGENEITY AND MECHANISMS OF DRUG RESISTANCE

COMORBIDITY IN TRAUMATIC BRAIN INJURY AND RISK OF ALL-CAUSE MORTALITY, FUNCTIONAL AND FINANCIAL BURDEN: A DECADE-LONG POPULATION BASED COHORT STUDY

GENETIC CORRECTION OF A NOVEL "KNOCK-IN" MOUSE MODEL FOR FARBER DISEASE

TARGETING OVARIAN CANCER WITH PORPHYSOME NANOTECHNOLOGY

TARGETING OVARIAN CANCER WITH PORPHYSOME NANOTECHNOLOGY

ENDOGENOUS OPIOID SYSTEM IN PANIC DISORDER: 5-DOSE NALOXONE PROCEDURE AND SSRI TX

IDENTIFICATION OF MOLECULAR BIOMARKERS FOR INVASIVE GLIOBLASTOMA CELL STATES AND TUMOR MICROENVIRONMENT MODULATION

A LONGITUDINAL POPULATION-BASED BIRTH COHORT STUDY TO UNDERSTAND THE PAST, PRESENT, AND FUTURE OF CHILDREN AND YOUTH WITH TRAUMATIC BRAIN INJURY - PROJECT SUMMARY/ABSTRACT TRAUMATIC BRAIN INJURY (TBI) SUSTAINED DURING CHILDHOOD AND ADOLESCENCE (HEREIN REFERRED TO AS ‘PEDIATRIC TBI’) CAN RESULT IN LONG-TERM NEGATIVE OUTCOMES. PEDIATRIC TBI MAY COMPROMISE BOTH SKILLS THAT ARE DEVELOPING AT THE TIME OF INJURY AND SKILLS THAT ARE YET TO DEVELOP. IMPORTANTLY, THE CONSEQUENCES OF PEDIATRIC TBI MAY NOT BE IMMEDIATELY APPARENT, WITH PROBLEMS ONLY MANIFESTING YEARS POST-INJURY WHEN THESE CHILDREN ARE UNABLE TO MEET DEVELOPMENTAL MILESTONES. LONGITUDINAL DATA THAT FOLLOW CHILDREN WITH TBI INTO ADULTHOOD IS SCARCE, A LIMITATION ALSO RECOGNIZED BY THE CENTERS FOR DISEASE CONTROL AND PREVENTION AND STATED IN ITS REPORT TO CONGRESS. THESE DATA ARE IMPORTANT BECAUSE TBI IS NOT A SINGLE EVENT BUT RATHER, A CHRONIC DISEASE WITH LIFELONG CONSEQUENCE AFFECTING INDIVIDUALS (E.G., SECONDARY HEALTH CONDITIONS) AS WELL AS SOCIETY AS A WHOLE (E.G., INCREASED HEALTHCARE USE). ACCESS TO AND USE OF HEALTHCARE SERVICES IS ALSO SIGNIFICANTLY REDUCED AS ADOLESCENTS TRANSITION TO ADULT CARE, RESULTING IN WORSE HEALTH OUTCOMES AND UNMET HEALTHCARE NEEDS. IN ADDITION, THERE IS LIMITED DATA BY SEX AND/OR GENDER EVEN THOUGH THERE IS EVIDENCE THAT SEX (BIOLOGICAL ATTRIBUTES) AND GENDER (SOCIAL-CULTURAL FACTORS) INFLUENCE HEALTH SERVICE USE AND OUTCOMES AFTER TBI. FINALLY, THE TRUE BURDEN OF PEDIATRIC TBI IS CURRENTLY SIGNIFICANTLY UNDERESTIMATED BECAUSE MOST DATA ON THE INCIDENCE OF PEDIATRIC TBI ARE BASED ON HEALTHCARE RECEIVED IN THE EMERGENCY DEPARTMENT OR HOSPITAL SETTINGS EVEN THOUGH UP TO 90% OF PEDIATRIC TBIS ARE TREATED IN PRIMARY CARE, URGENT CARE, AND SPECIALTY CARE. THE OVERARCHING GOAL OF THIS PROJECT IS TO LEVERAGE EXISTING LARGE DATASETS TO BUILD A DYNAMIC POPULATION-BASED BIRTH COHORT OF AT LEAST 4 MILLION LIVE BIRTHS IN ONTARIO, CANADA, FROM 1992 TO DECEMBER 2020 (ANTICIPATED START OF THE FUNDING) AND UP TO 28 YEARS OF FOLLOW-UP DATA. THIS BIRTH COHORT WILL BE THE FIRST OF ITS KIND IN THE UNITED STATES OR CANADA AND AS ADDITIONAL YEARS OF DATA BECOME AVAILABLE, THE SAMPLE SIZE OF THE BIRTH COHORT AND FOLLOW-UP PERIOD WILL LIKEWISE INCREASE. ALL RESIDENTS OF ONTARIO RECEIVE MEDICALLY NECESSARY HEALTH SERVICES FROM A PUBLICLY FUNDED HEALTH SYSTEM AND COLLECTION OF THESE DATA ARE MANDATORY. AS SUCH, THIS BIRTH COHORT WILL CAPTURE ALL INTERACTIONS WITH THE PUBLICLY FUNDED HEALTH SYSTEM FROM BIRTH UNTIL THE END OF FOLLOW-UP PERIOD, MIGRATION, OR DEATH. THE SPECIFIC RESEARCH OBJECTIVES ARE TO USE THIS BIRTH COHORT TO: (1) PROVIDE COMPREHENSIVE, SEX-SPECIFIC ESTIMATES OF THE INCIDENCE OF PEDIATRIC TBI; (2) DETERMINE THE FREQUENCY AND TYPES OF SECONDARY HEALTH CONDITIONS THAT OCCUR POST-PEDIATRIC TBI; AND (3) IDENTIFY THE PATTERNS OF HEALTHCARE USE POST-PEDIATRIC TBI FROM CHILDHOOD TO ADULTHOOD. THIS EARLY CAREER AWARD WILL ENABLE THE PI TO BUILD THIS BIRTH COHORT TO GENERATE RIGOROUS PRELIMINARY DATA THAT WILL INCREASE THE LIKELIHOOD OF SUCCESSFUL R01 APPLICATIONS AND EXTEND HER INDEPENDENT PROGRAM OF RESEARCH TO UNDERSTAND THE LONG- TERM HEALTH OUTCOMES AFTER PEDIATRIC TBI.

THE LONG NONCODING RNA CRNDE IN HCC-INDUCED IMMUNE SUPPRESSION

SEQUENTIAL INFECTION OF LABORATORY MICE FOR ENHANCED CANCER AND IMMUNOTHERAPY TRANSLATION - ABSTRACT MOUSE MODELS HAVE BEEN TREMENDOUSLY IMPORTANT TO UNDERSTAND AND DEVELOP TREATMENTS FOR HUMANS. YET, FROM AN IMMUNE PERSPECTIVE, MOUSE MODELS RESEMBLE AN IMMATURE IMMUNE SYSTEM, INCLUDING LACK OF MICROBIOTA ADAPTATIONS, INFECTIONS, AND VACCINATIONS THAT HUMANS ENCOUNTER EARLY IN LIFE TO SHAPE IMMUNE MATURATION. USE OF WILD-CAUGHT MICE THAT HAVE A MORE ADULT-LIKE IMMUNE SYSTEM HAS HELPED TO BETTER UNDERSTAND THE ADULT IMMUNE RESPONSE; HOWEVER, THESE MICE HAVE A SERIES OF PRACTICAL AND GENETIC ISSUES THAT PRECLUDE THEIR WIDESPREAD USE. WE HYPOTHESIZE THAT THE NEONATAL LIKE IMMUNE SYSTEM IN SPECIFIC PATHOGEN FREE (SPF) MICE THAT ARE NORMALLY USED IN THE LABORATORY UNDERLIES MANY OF THE DIFFERENCES OBSERVED BETWEEN MOUSE AND HUMAN ANTI-TUMOR RESPONSES AND THE TRANSLATABILITY OF THERAPEUTIC APPROACHES. TO OVERCOME THIS, WE WILL ADAPT AND DEVELOP A STRATEGY TO PRODUCE LAB-GENERATED “WILD-LIKE” MICE THAT MIMIC THE IMMUNE RESPONSE OBSERVED IN ADULTS. WE PROPOSE THAT THESE LAB-GENERATED “WILD-LIKE” MICE WILL RECAPITULATE THE ADULT HUMAN IMMUNE SYSTEM AND MIMIC THE RESPONSES TO CANCER AND IMMUNOTHERAPY OBSERVED IN HUMANS. THIS APPROACH OF IMMUNE EDUCATION IS PERFORMED ON OTHERWISE WILD-TYPE MICE, ENABLING WIDE-SPREAD ADOPTION TO FOSTER CANCER STUDIES.

VITAMIN D PHARMACOGENETIC EPIDEMIOLOGY AND HEAD AND NECK CANCER SURVIVORSHIP

MRI GUIDED AND TUMOR TARGETED HDR BRACHYTHERAPY FOR RECURRENT PROSTATE CANCER

PHOTODYNAMIC MOLECULAR BEACONS: AN IMAGE-GUIDED THERAPEUTIC APPROACH TO BREAST CANCER VERTEBRAL METASTASES

NEW APPROACH TO IDENTIFY NOVEL REGULATORS OF MYC ONCOPROTEIN STABILITY

DEVELOPMENT OF A NOVEL NMR-BASED RHEB GTPASE ASSAY AND MOLECULAR CHARACTERIZATION OF TSC2 GAP ACTIVITY