Cilia and Valvular Heart Disease
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Principal Investigator: Russell Norris Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA Fiscal Year: 2024 Award: $559,990 Funding agency: National Heart Lung and Blood Institute PROJECT SUMMARY Based on genetic and cellular discoveries made in the PI lab and his collaborators, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Data presented in the proposal are an evolution of our studies presented in the first round of funding and show that mutations in the DZIP1 gene cause a very common heart valve disease (i.e., mitral valve prolapse) and can be caused by errors in how valve tissue forms during development. These discoveries have led to a novel concept that cilia are involved in valve development. While the function of DZIP1 is a focus of our studies in this proposal, we will also define new mechanisms by which the cardiac valves establish a trilaminar ECM organization and how this can feed back to the cells to suppress ciliogenesis in specific regions of the valve. Our studies will provide unique opportunities to answer questions about heart-valve diseases that heretofore have been impossible to answer using even state-of-the- art biological and genetic approaches. Valvular heart disease is a serious clinical problem, affecting 5-7% of the human population. Its complications include congestive heart failure, endocarditis, atrial arrhythmias, and sudden death. There are no known non- surgical cures for this group of disease. The proposed work capitalizes on previously unrecognized genetic data collected from heart valve disease patients; studies in the mouse show that this class of genes is an important and previously unrecognized contributor to valve structural development and disease pathogenesis. The uncovering of this particular disease gene and the processes it regulates holds great potential for future remedial or therapeutic insight towards regeneration or formation of mechanically stable valve tissue that will be beneficial to valvular heart disease patients. Terms: <17p13><3-D><3-Dimensional><3D><Affect><Arrhythmia><Atrial><Back><Barlows Syndrome><Bicuspid Valve><Biochemical><Biologic Models><Biological><Biological Models><Biology><Biomechanics><Biomedical Engineering><Body Tissues><Cardiac><Cardiac Arrhythmia><Cardiac Atrium><Cardiac Failure Congestive><Cardiac Valves><Cardiac development><Causality><Cell Body><Cell-Extracellular Matrix><Cells><Chordae Tendineae><Chromatin><Cilia><Clinical><Code><Coding System><Collagen><Congestive Heart Failure><Connexin 43><Connexin43><Cx43><Data><Defect><Deposit><Deposition><Development><Disease><Disorder><Dorsum><ECM><Endocarditis><Enhancers><Etiology><Event><Evolution><Extracellular Matrix><Extracellular Matrix Proteins><Failure><Fibroblasts><Floppy Mitral Valve><Funding><Future><GWA study><GWAS><General Population><General Public><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic study><Goals><Grant><Heart Arrhythmias><Heart Atrium><Heart Decompensation><Heart Valve Diseases><Heart Valves><Heart failure><Human><Hyperplasia><Hyperplastic><Individual><Light><Link><Marfan Syndrome><Mechanical Stress><Mechanics><Medial><Mesenchymal><Mesenchymas><Mesenchyme><Mice><Mice Mammals><Mitral Click-Murmur Syndrome><Mitral Incompetence><Mitral Insufficiency><Mitral Regurgitation><Mitral Valve><Mitral Valve Incompetence><Mitral Valve Insufficiency><Mitral Valve Prolapse><Mitral Valve Regurgitation><Model System><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><Natural regeneration><Operative Procedures><Operative Surgical Procedures><Pathogenesis><Pathway interactions><Patients><Phenotype><Photoradiation><Play><Population><Process><Procidentia><Production><Prolapse><Proteins><Proteoglycan><Ptosis><RNA Splicing><Regeneration><Research><Role><Splicing><Stress><Structure><Structure of chordae tendineae cordis><Sudden Death><Surgical><Surgical Interventions><Surgical Procedure><Syndrome><Systole><Systolic Click-Murmur Syndrome><Testing><Therapeutic><Time><Tissues><Transcription Initiation Site><Transcription Start Site><Valvular Heart Diseases><Valvular Heart Disorder><Ventricular><Work><atrium><bio-engineered><bio-engineers><bioengineering><biologic><biological engineering><biomechanical><cardiac failure><cardiac valve disease><cardiac valve disorder><cardiac valvular disease><cardiogenesis><causation><chronic heart failure><ciliogenesis><cilium biogenesis><degenerative valvular heart disease><developmental><disease causation><fibrogenesis><functional genomics><genetic approach><genetic strategy><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><heart development><heart formation><heart valve disorder><insight><interstitial cell><mechanic><mechanical><mutant><novel><pathway><patient population><premature><prematurity><regenerate><repair><repaired><social role><stem><sudden cardiac death><surgery><three dimensional><whole genome association analysis><whole genome association studies><whole genome association study>