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Cilia and Valvular Heart Disease

纤毛和瓣膜性心脏病

基本信息

批准号：
10594935
负责人：
Russell Norris
金额：
$ 57.14万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594935
关键词：
17p13 3-Dimensional Affect Arrhythmia Back Biochemical Biological Biological Models Biology Biomechanics Biomedical Engineering Cardiac Cells Chromatin Cilia Clinical Code Collagen Congestive Heart Failure Connexin 43 Data Defect Deposition Development Disease Endocarditis Enhancers Etiology Event Evolution Extracellular Matrix Extracellular Matrix Proteins Failure Fibroblasts Funding Future General Population Genes Genetic Genetic study Goals Grant Heart Atrium Heart Valve Diseases Heart Valves Heart failure Human Hyperplasia Individual Light Link Marfan Syndrome Mechanical Stress Mechanics Medial Mesenchymal Mesenchyme Mitral Valve Mitral Valve Insufficiency Mitral Valve Prolapse Modeling Molecular Mus Mutation Natural regeneration Operative Surgical Procedures Pathogenesis Pathway interactions Patients Phenotype Play Population Process Production Proteins Proteoglycan Ptosis RNA Splicing Research Role Stress Structure Structure of chordae tendineae cordis Sudden Death Syndrome Systole Testing Therapeutic Time Tissues Transcription Initiation Site Ventricular Work cardiogenesis cilium biogenesis fibrogenesis functional genomics genetic approach genome wide association study insight interstitial cell mutant novel patient population premature repaired stem sudden cardiac death

项目摘要

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.

项目总结