Texas Heart Institute

CARDIOVASCULAR CELL THERAPY RESEARCH NETWORK

HIPPO AND WNT SIGNALING IN CARDIAC REGENERATION

EFFECTS OF A PULSE INDUCED BY A CONSTANT-FLOW TOTAL CARDIAC REPLACEMENT DEVICE

DEVELOPMENT OF A FULLY-IMPLANTABLE VENTRICULAR ASSIST DEVICE FOR NEONATES AND CHILDREN WITH HEART FAILURE - WITH MAGNETIC LEVITATION TO IMPROVE HEMOCOMPATIBILITY

A NOVEL APPROACH TO CARDIAC REPLACEMENT WITH CONTINUOUS FLOW PUMPS

LEADLESS WIRELESSLY POWERED PACEMAKER FOR MULTI CHAMBER PACING USING MINIATURIZED PACING AND SENSING NODE

COMBINED STEM CELL AND ASSIST DEVICE THERAPY FOR HEART FAILURE

CARDIOVASCULAR CELL THERAPY RESEARCH NETWORK

TARGETING INTEGRIN SIGNALING IN ATHEROSCLEROSIS - CARDIOVASCULAR DISEASE REMAINS THE LEADING CAUSE OF DEATH, WORLDWIDE. THE MOST COMMON UNDERLYING CAUSE OF ISCHEMIC HEART DISEASE AND STROKE IS ATHEROSCLEROSIS. THREE SEMINAL STUDIES, THE CANAKINUMAB ANTI-INFLAMMATORY THROMBOSIS OUTCOMES STUDY (CANTOS), LOW DOSE COLCHICINE FOR SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE (LODOCO2), AND THE COLCHICINE CARDIOVASCULAR OUTCOMES TRIAL (COLCOT), HAVE PROVEN THE HYPOTHESIS THAT ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE, AND THAT TARGETING MECHANISMS OF INFLAMMATION CAN REDUCE MAJOR ADVERSE CARDIAC EVENTS INDEPENDENT OF LIPID LOWERING. THE WORK PROPOSED HERE REPRESENTS A DRUG DISCOVERY AND DEVELOPMENT PROGRAM DESIGNED TO TARGET RESIDUAL INFLAMMATORY RISK IN PATIENTS WITH ATHEROSCLEROSIS. IT IS IN RESPONSE TO THE FUNDING OPPORTUNITY ANNOUNCEMENT RFA-HL-23-011 TITLED “CATALYZE: PRODUCT DEFINITION FOR SMALL MOLECULES AND BIOLOGICS - TARGET IDENTIFICATION AND VALIDATION, AND PRELIMINARY PRODUCT/LEAD SERIES IDENTIFICATION (R61/R33).” INTERLEUKIN-1SS (IL-1SS) WAS THE TARGET OF CANAKINUMAB IN THE CANTOS TRIAL. INFLAMMATORY CELLS LIKE ACTIVATED MONOCYTES AND MACROPHAGE ARE A SIGNIFICANT SOURCE OF INTERLEUKIN-1SS IN ATHEROSCLEROTIC PLAQUES. ITS TRANSCRIPTION IS UNDER TIGHT CONTROL, AND MAXIMUM EXPRESSION OF THIS CYTOKINE IN INFLAMMATORY LEUKOCYTES REQUIRES ADHESION DEPENDENT SIGNALING THROUGH INTEGRINS. INTEGRINS TRANSMIT SIGNALS INTO CELLS THROUGH DIRECT INTERACTIONS BETWEEN THEIR CYTOPLASMIC DOMAINS AND INTRACELLULAR EFFECTORS. INTEGRIN SS-CHAIN CYTOPLASMIC DOMAINS INTERACT DIRECTLY WITH THE NON-RECEPTOR TYROSINE KINASE SYK, WHICH IS AN ESSENTIAL KINASE IN THE PRODUCTION OF IL-1SS. IN PREVIOUS WORK, WE DETERMINED THAT SS-CHAIN CYTOPLASMIC DOMAIN INTERACTIONS WITH SYK WERE DRUGGABLE, AND AN ANTAGONIST OF THIS INTERACTION COULD PREVENT INTEGRIN MEDIATED UPREGULATION OF IL-1SS IN MONOCYTES. IN THE CURRENT PROPOSAL WE SEEK TO EXTEND THIS WORK BY PERFORMING A STRUCTURE-GUIDED VIRTUAL SCREEN OF OVER 10 MILLION COMPOUNDS TO IDENTIFY POTENT AND CELL-PERMEABLE DRUGS THAT CAN BE USED AS STARTING POINTS IN DRUG DISCOVERY AND DEVELOPMENT. OUR OBJECTIVE IN THE R61 COMPONENT OF THIS AWARD IS TO IDENTIFY COMPOUNDS FROM MODELING AND MOLECULAR DYNAMICS SIMULATIONS THAT CAN BE VALIDATED IN BOTH CELL-FREE, AND CELL-BASED ASSAYS OF INTEGRIN:SYK INTERACTIONS. ONCE STRICT “HIT” CRITERIA HAVE BEEN MET, THEY WILL ENTER INTO THE R33 COMPONENT OF THIS AWARD MECHANISM FOR ASSESSMENT OF POTENTIAL TOXICITIES, PHARMACOKINETICS, AND EFFICACY IN AN ACUTE MODEL OF INFLAMMATION IN MICE. THE STUDIES PROPOSED HERE WILL IDENTIFY A LEAD SERIES OF COMPOUNDS FOR DRUG DEVELOPMENT, WITH THE ULTIMATE GOAL BEING TO DEVELOP A NOVEL, FIRST-IN-CLASS APPROACH TO PHARMACOLOGICALLY TARGET RESIDUAL INFLAMMATORY RISK. CANTOS, LODOCO2, AND COLCOT DEMONSTRATED THAT TARGETING IL-1SS EITHER DIRECTLY OR INDIRECTLY IS A VIABLE APPROACH TO TREAT RESIDUAL INFLAMMATORY RISK IN ATHEROSCLEROSIS. THE PROPOSED APPROACH WOULD TARGET UPSTREAM SIGNALS IN THE REGULATION OF IL-1SS IN INFLAMMATORY LEUKOCYTES.

HTS PLATFORM FOR IDENTIFICATION OF REGULATORS OF CELL ADHESION MOLECULE SIGNALING

OPTIMIZATION OF SMALL MOLECULE INTEGRIN ACTIVATORS TO ENHANCE CORD BLOOD TRANSPLANT - PROJECT SUMMARY THIS PROPOSAL IS IN RESPONSE TO THE FUNDING OPPORTUNITY ANNOUNCEMENT RFA-HL-20-027 FOR THE CATALYZE: PRODUCT DEFINITION FOR SMALL MOLECULES AND BIOLOGICS - PRELIMINARY PRODUCT/LEAD SERIES IDENTIFICATION (R33 - CLINICAL TRIAL NOT ALLOWED) GRANTING MECHANISM. HEMATOPOIETIC STEM CELL TRANSPLANTATION HAS BECOME A PREFERRED TREATMENT FOR HEMATOLOGICAL MALIGNANCIES AND CERTAIN GENETIC DISORDERS. UMBILICAL CORD BLOOD HAS BECOME AN APPEALING ALTERNATIVE TO BONE MARROW OR PERIPHERAL BLOOD AS A SOURCE OF HEMATOPOIETIC STEM CELLS FOR TRANSPLANT. DUE TO A LESS STRINGENT HLA MATCH REQUIREMENT, CORD BLOOD TRANSPLANT HAS ALLOWED PATIENTS TO BE TREATED THAT OTHERWISE COULD NOT FIND A SUITABLE DONOR. UNFORTUNATELY, THERE ARE FEWER STEM CELLS IN THESE PREPARATIONS WHICH RESULTS IN DELAYED RATES OF IMMUNOLOGICAL RECONSTITUTION. THIS CAN LEAD TO A HIGHER INCIDENCE OF OPPORTUNISTIC INFECTIONS WHICH INCREASES THE RATE OF GRAFT FAILURES AND TRANSPLANT RELATED MORTALITIES. FINDING A MEANS TO IMPROVE THE RATE OF IMMUNE RECONSTITUTION WITH CORD BLOOD TRANSPLANTS WOULD TRANSLATE TO IMPROVED OUTCOMES AS WELL AS BROADER APPLICABILITY TO ADULT PATIENTS. EFFORTS TO IMPROVE THE RATE OF ENGRAFTMENT OF CORD BLOOD CELLS INCLUDE TARGETING THE CELL ADHESION CASCADE WHICH MEDIATES CELL HOMING, EXTRAVASATION AND RETENTION IN THE BONE MARROW. THIS PROCESS IS COORDINATED THROUGH THE FUNCTION OF CHEMOKINES AS WELL AS THE SELECTIN AND INTEGRIN FAMILIES OF CELL ADHESION MOLECULES. PROMISING RESULTS HAVE BEEN GENERATED BY TREATING THE CELLS EX-VIVO TO IMPROVE THE FUNCTION OF THE SELECTIN- AND CHEMOKINE-MEDIATED PROCESSES. A DRAWBACK TO THESE PRECONDITIONING STEPS IS THEY REQUIRE ADDITIONAL TIME, EXPERTISE AND EXPENSE. AS YET THE INTEGRINS HAVE NOT BEEN TARGETED DUE TO A LACK OF SUITABLE REAGENTS. WE HAVE DEVELOPED A FAMILY OF SMALL MOLECULES THAT CAN ACTIVATE INTEGRINS ON CORD BLOOD CELLS, FACILITATING THEIR INTERACTION WITH THEIR COUNTER-RECEPTORS IN THE BONE MARROW. WE HAVE DEMONSTRATED PROOF-OF- CONCEPT USING A REPRESENTATIVE MEMBER OF THE FAMILY THAT DOSING SUCH A COMPOUND FOLLOWING TRANSPLANT OF HUMAN CD34+ CORD BLOOD CELLS INTO NOD-SCID MICE LEADS TO INCREASED ENGRAFTMENT OF CD34+ CELLS IN THE BONE MARROW AND INCREASED CD45+ CELL COUNTS IN PERIPHERAL BLOOD. THESE COMPOUNDS CAN BE DOSED INDEPENDENTLY OF THE CELLS AND ARE TYPICALLY INEXPENSIVE TO SYNTHESIZE ON A LARGE-SCALE. THIS WOULD HAVE AN ADVANTAGE OVER OTHER TECHNOLOGIES AS NO PRECONDITIONING OR MANIPULATIONS OF THE CELLS WOULD BE REQUIRED MEANING A MORE AFFORDABLE AND UNIVERSALLY TRANSLATABLE THERAPY. ALTHOUGH PROMISING, OUR LEAD COMPOUND SUFFERS FROM LOW ORAL BIOAVAILABILITY IN PART DUE TO IT BEING METABOLIZED BY CYP3A4. THESE ISSUES MAKE IT LESS ATTRACTIVE FOR CORD BLOOD TRANSPLANT DUE TO POTENTIAL DRUG-DRUG INTERACTIONS AS WELL AS THE MULTI-DAY DOSING REGIMEN THAT WILL LIKELY BE REQUIRED BASED ON PRECLINICAL ANIMAL MODELS. THIS R33 GRANT PROPOSAL INCLUDES AIMS TO ADDRESS THE STRUCTURAL ALERTS FOR CYP3A4 ACTIVITY TO GENERATE A NEXT GENERATION COMPOUND WITH DECREASED METABOLIC LIABILITIES AND IMPROVED ORAL PHARMACOKINETICS. IF SUCCESSFUL, THIS SHOULD RESULT IN IDENTIFYING A CLINICAL CANDIDATE TO PROGRESS INTO INVESTIGATIONAL NEW DRUG (IND)-ENABLING STUDIES.

NEW CARDIOVASCULAR RESEARCH SCIENTIST FOR MOLECULAR AND CELLULAR BIOLOGY CORE

PROSTACYCLIN-SECRETING CELLS AS THERAPY FOR PULMONARY ARTERY HYPERTENSION

GADONANOTUBES AS NEW MRI NANOLABELS FOR STEM CELL TRACKING

SAASTRONAUTS ARE FACED WITH SEVERAL HEALTH RISKS DURING BOTH SHORT- AND LONG-DURATION SPACEFLIGHT DUE TO THE SPACE ENVIRONMENT. MICROGRAVITY ITSELF S

MAGNETIC LEVITATION TO IMPROVE HEMOCOMPATIBILITY OF A PERCUTANEOUS LVAD (MICROVASC) FOR EARLY INTERVENTION

USING A CARDIAC MICROTISSUE SYSTEM TO EVALUATE AND REPLICATE CLINICAL THERAPY RESPONSES USING PATIENT CELL-DERIVED EXOSOMES

ESTABLISHING AUTOMATED CRYOPRESERVATION SYSTEM FOR BIOSPECIMEN STORAGE - BIOBANKING HAS BEEN PLAYING AN INCREASINGLY ESSENTIAL ROLE IN BIOMEDICAL RESEARCH, GROWING FROM SIMPLE BIOSPECIMEN REPOSITORIES TO LARGE COMPLEX INFRASTRUCTURE-BASED SYSTEMS. WITH THE EMERGENCE OF OMICS-BASED TECHNOLOGIES AND THE EVER-INCREASING DEMAND OF BIOSPECIMENS, THERE IS A RECENT SURGE IN THE NUMBER OF BIOREPOSITORIES. CONSEQUENTLY, BIOREPOSITORIES ARE UNDERGOING MODERNIZATION BY IMPLEMENTING STATE-OF-THE-ART FEATURES OF SAMPLE ACQUISITION, QUALITY CONTROL, STORAGE AND PRESERVATION, AND ANALYSIS OF DISEASE-SPECIFIC BIOMARKERS, SUPPLEMENTED WITH WELL-ANNOTATED DEMOGRAPHICS AND CLINICAL/BIOLOGICAL DATA, WITH THE GOAL OF PRECISION MEDICINE OUTCOMES. THE TEXAS HEART INSTITUTE (THI)’S COLLEGE OF AMERICAN PATHOLOGISTS-ACCREDITED AND US FOOD AND DRUG ADMINISTRATION- AND INTERNATIONAL SOCIETY FOR BIOLOGICAL AND ENVIRONMENTAL REPOSITORIES -COMPLIANT BIOREPOSITORY AND BIOSPECIMEN PROFILING CORE LABORATORY (THI-BRC) HAS A LARGE LIQUID NITROGEN (LN2) CRYOPRESERVATION SYSTEM FOR LONG-TERM PRESERVATION OF BIOSPECIMENS. AS A SHARED RESOURCE FACILITY, THI-BRC IS PROVIDING VALUABLE SERVICE, SUCH AS SAMPLE (MAINLY CARDIOVASCULAR) COLLECTION, QUALITY-CONTROL, PROCESSING, STORAGE AND PRESERVATION, ANALYSIS, AND INVENTORY MAINTENANCE, TO INTERNAL THI INVESTIGATORS AND COLLABORATORS THROUGHOUT THE NATION, SUPPORTING VARIOUS FEDERAL/STATE/NONGOVERNMENT-FUNDED BASIC SCIENCE AND TRANSLATIONAL RESEARCH PROJECTS AND CLINICAL TRIALS. GIVEN THE INCREASING NEED OF LARGE NUMBERS OF HIGH-QUALITY SAMPLES BY OUR INVESTIGATORS AND COLLABORATORS, PARTICULAR ATTENTION IS NEEDED FOR SAMPLE ACQUISITION, PREPARATION, PRESERVATION, RETRIEVAL, AND INVENTORY MANAGEMENT, WHICH CAN BE MET BY INSTALLING AN AUTOMATED CRYOPRESERVATION WORKSTATION. THIS PROJECT WILL INVOLVE INSTALLATION OF THE BIOSTORE CRYO III AUTOMATED CRYOPRESERVATION SYSTEM IN THI-BRC AND ITS INTEGRATION INTO OUR BIOREPOSITORY CURRENT PRACTICES, INCLUDING THE DEVELOPMENT OF EQUIPMENT-SPECIFIC STANDARD OPERATING PROCEDURES (AIM 1), AND TRAINING THI-BRC PERSONNEL IN THE USE AND MAINTENANCE OF THIS AUTOMATED CRYOPRESERVATION SYSTEM AND ADVERTISING TO THE RESEARCH COMMUNITY THE AVAILABILITY OF THIS MODERNIZED STORAGE SYSTEM WITH INCREASED SAMPLE STORAGE CAPABILITIES AND QUALITY CONTROL (AIM 2). IMPORTANTLY, THE PROPOSED SYSTEM DOES NOT REQUIRE ANY CHANGES TO THE CURRENT INFRASTRUCTURE. AUTOMATED CRYOPRESERVATION WILL BE IMPLEMENTED TO VARYING DEGREES AT VARIOUS STAGES OF OUR BIOREPOSITORY OPERATIONS TO IMPROVE SAMPLE ACCESS, COST, AND THROUGHPUT, OFFERING BOTH QUANTITATIVE AND SUBSTANTIAL BENEFITS TO THE WORKFLOW, SUCH AS INTEGRATED SAMPLE TRACEABILITY, SECURE STORAGE, INCREASED RETRIEVAL SPEED, AND SAMPLE PRESERVATION. THE OPERATION WORKFLOW IN OUR BIOREPOSITORY WILL BE STANDARDIZED AND CONTROLLED WHILE REDUCING THE TIME OF RACK EXPOSURE OUTSIDE THE LN2 FREEZER TEMPERATURE. ALONG WITH MITIGATING TEMPERATURE FLUCTUATION OF NOT-INTENDED-TO-BE-THAWED BIOSPECIMENS, THEREBY MAINTAINING STRUCTURAL INTEGRITY AND FUNCTIONAL ATTRIBUTES OF THE BIOSPECIMENS, THE AUTOMATED CRYOPRESERVATION SYSTEM WILL OVERCOME TIME-CONSUMING MANUAL PROCESSES, IMPROVE THE EFFICIENCY OF WORKFLOW, AND BENEFIT THI’S INTERNAL AND EXTERNAL INVESTIGATORS’ BASIC AND TRANSLATIONAL RESEARCH INITIATIVES ON CARDIOVASCULAR HEALTH.

HEALTH CARE AND OTHER FACILITIES

A PATIENT-SPECIFIC ANALYSIS FRAMEWORK FOR ASSESSING STROKE RISK IN PEDIATRIC MOYAMOYA DISEASE