Cilia and Valvular Heart Disease

纤毛和瓣膜性心脏病

• 批准号: 10444340
• 负责人: Russell Norris
• 金额: $ 58.37万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/10444340
• 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; 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; Lead; Light; Link; Marfan Syndrome; Mechanical Stress; Mechanics; 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; base; cardiogenesis; cilium biogenesis; fibrogenesis; functional genomics; genetic approach; genome wide association study; insight; interstitial cell; mutant; novel; patient population; premature; rare condition; repaired; stem; sudden cardiac death

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.

项目概要 基于 PI 实验室及其合作者的遗传和细胞发现，该提案的重点是 对于心脏瓣膜的形成至关重要的新机制。提案中提供的数据是一种演变 我们在第一轮资助中提出的研究表明，DZIP1 基因的突变会导致非常严重的后果。 常见的心脏瓣膜疾病（即二尖瓣脱垂），可能是由瓣膜组织形成错误引起的 在开发过程中。这些发现提出了一个新概念：纤毛参与瓣膜发育。 虽然 DZIP1 的功能是我们在本提案中研究的重点，但我们还将通过以下方式定义新的机制： 心脏瓣膜建立了三层 ECM 组织，以及它如何反馈给细胞 抑制瓣膜特定区域的纤毛生成。我们的研究将提供独特的机会来回答 有关心脏瓣膜疾病的问题迄今为止即使使用最新技术也无法回答 艺术生物学和遗传学方法。 瓣膜性心脏病是一个严重的临床问题，影响着 5-7% 的人口。它的并发症 包括充血性心力衰竭、心内膜炎、房性心律失常和猝死。没有已知的非 手术治疗此类疾病。拟议的工作利用了以前未被识别的遗传数据 从心脏瓣膜疾病患者收集；对小鼠的研究表明，这类基因是重要的 以及以前未被认识到的瓣膜结构发育和疾病发病机制的贡献者。这 揭示这种特定的疾病基因及其调节过程对于未来的治疗具有巨大的潜力 或对机械稳定瓣膜组织的再生或形成的治疗见解将是有益的 对于瓣膜性心脏病患者。