R01HL180627

CELL-TYPE SPECIFIC MECHANISMS OF MITRAL VALVE PROLAPSE - PROJECT SUMMARY THE HEART CONSISTS OF A BROAD SPECTRUM OF CARDIAC CELL TYPES THAT FORM DISTINCT CARDIAC STRUCTURES CRITICAL FOR MAINTAINING HEART FUNCTION. THESE CELL POPULATIONS INCLUDE NOT ONLY CARDIOMYOCYTES, CARDIAC FIBROBLASTS, EPICARDIAL CELLS, ENDOTHELIAL/ENDOCARDIAL CELLS AND SMOOTH MUSCLE CELLS, BUT ALSO MORE SPECIALIZED CELL TYPES COMPRISING THE CARDIAC VALVES, CARDIAC CONDUCTION SYSTEM, ETC. THUS, MAINTAINING THE FUNCTION AND HOMEOSTASIS OF THESE CELL TYPES IS CRUCIAL FOR OPTIMAL HEART PERFORMANCE, AND DISRUPTING THEIR OVERALL MAINTENANCE CAN RESULT IN DISTINCT HEART DISEASES INCLUDING MITRAL VALVE PROLAPSE (MVP), ONE OF THE MOST FREQUENT VALVULAR HEART DISEASES (VHD) THAT HAS A 2-3% PREVALENCE IN THE GENERAL POPULATION. HOWEVER, DESPITE RECENT GENETIC STUDIES IDENTIFYING POTENTIAL GENETIC LOCI ASSOCIATED WITH MVP, WHAT ARE THE SPECIFIC CELL LINEAGES AFFECTED DURING MVP AND HOW DO GENE REGULATORY NETWORKS (GRNS) CONTROL GENETIC PROGRAMS THAT DIRECT THEIR PATHOLOGIC OUTCOMES ARE KEY BIOMEDICAL QUESTIONS THAT REMAIN TO BE ELUCIDATED. THUS, TO EXAMINE SPECIFIC CELL-TYPES PARTICIPATING IN VHDS, PARTICULARLY MVP, WE PROPOSE TO IMPLEMENT JOINT SINGLE CELL/NUCLEAR (SC/SN) RNA-SEQ AND ATAC-SEQ TECHNOLOGIES (I.E. SINGLE CELL MULTI-OMICS) ON NORMAL AND MVP/DISEASED HUMAN MITRAL VALVES. IN ADDITION TO IDENTIFYING DISTINCT CV CELL-TYPES AND THEIR RELATED TRANSCRIPTIONAL PROFILES AND CHROMATIN LANDSCAPE, WE SEEK TO ELUCIDATE THE INTERACTIONS BETWEEN CELL-TYPE SPECIFIC CIS-REGULATORY ELEMENTS/CRES (E.G. ENHANCER-PROMOTER CONNECTIONS), WHICH MEDIATE THE GRNS THAT CONTROL HOW CRES DIRECT GENE EXPRESSION OF THESE CELL TYPES IN NORMAL AND MVP MITRAL VALVES. FURTHERMORE, BECAUSE STRUCTURAL FORM IS CRITICAL FOR MAINTAINING CARDIAC VALVE FUNCTION, WE PROPOSE TO FURTHER INVESTIGATE THE SPATIAL ORGANIZATION OF IDENTIFIED CELL TYPES IN THE MITRAL VALVES OF HUMAN HEARTS WITH AND WITHOUT MVP. THROUGH THESE MULTI- DISCIPLINARY INTEGRATIVE EFFORTS AND ANALYSES, WE PLAN TO EXAMINE THE HYPOTHESIS THAT CRES AND THEIR ENHANCER- PROMOTER INTERACTIONS DYNAMICALLY FUNCTION AND COORDINATE IN A CELL-TYPE SPECIFIC MANNER TO DIRECT LINEAGE- SPECIFIC GENE EXPRESSION DURING MITRAL VALVE HOMEOSTASIS AND MVP DEFECTS/DISEASE, AND ALTERING THESE HIGHLY- REGULATED CELL-TYPE SPECIFIC CRES AND GRNS, ESPECIALLY IN CARDIAC VALVE SPECIFIC CELL TYPES, CAN LEAD TO MVP AND POSSIBLY OTHER VHDS. SPECIFICALLY, WE PROPOSE TO 1) IDENTIFY HUMAN CARDIAC VALVULAR CELL-TYPES AND THEIR GENE REGULATORY PROGRAMS IN NORMAL AND MVP DEFECTIVE/DISEASED MITRAL VALVES; 2) INVESTIGATE THE SPATIAL ORGANIZATION OF THE DIVERSE CARDIOVASCULAR CELL TYPES OF NORMAL AND MVP DEFECTIVE/DISEASED MITRAL VALVES; AND 3) EXAMINE HOW PERTURBATIONS OF CELL-TYPE SPECIFIC CRES AND GRNS DURING MVP IMPACT CELL FUNCTION AND GENE EXPRESSION.

San Diego University Of California

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

La Jolla, California 92093 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)