Cilia and Valvular Heart Disease

纤毛和瓣膜性心脏病

• 批准号: 9276120
• 负责人: Russell Norris
• 金额: $ 37.38万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276120
• 关键词: Affect; Area; Arrhythmia; Biological; Biological Models; Cardiovascular system; Cell Differentiation process; Cell Polarity; Cell physiology; Cells; Cilia; Clinical; Collagen; Congestive Heart Failure; Data; Defect; Development; Disease; Endocarditis; Endocardium; Erinaceidae; Etiology; Exhibits; Future; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Heart Atrium; Heart Valve Diseases; Heart Valves; Human; Impairment; International; Knockout Mice; Laboratories; Ligands; Link; Mechanics; Mesenchyme; Mitral Valve; Mitral Valve Prolapse; Molecular; Morphogenesis; Morphology; Mus; Mutation; Natural regeneration; Nuclear Translocation; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Population; Process; Regulation; Research Personnel; Signal Transduction; Stem cells; Sudden Death; Testing; Therapeutic; Tissues; Work; aortic valve disorder; base; bicuspid aortic valve; cardiogenesis; ciliopathy; cilium biogenesis; experimental study; fetal; genetic approach; genome-wide; insight; interstitial cell; mouse model; novel; paracrine; receptor; smoothened signaling pathway; therapy development; tool; transcription factor; transcriptome; whole genome

Project Summary Based on genetic and cellular discoveries made in the PI's lab and his collaborators, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Data presented in the proposal show that mutations in the DCHS1 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 the identification of cilia as a critical and unexplored area of valve development, and are the basis for this proposal. 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，该提案重点关注 对于心脏瓣膜的形成至关重要的新机制。提案中提供的数据表明 DCHS1 基因突变会导致一种非常常见的心脏瓣膜疾病（即二尖瓣脱垂），并且可以 是由瓣膜组织在发育过程中形成的错误引起的。这些发现导致 将纤毛确定为瓣膜发育的关键且未经探索的领域，并且是该提案的基础。 我们的研究将为回答迄今为止有关心脏瓣膜疾病的问题提供独特的机会 即使使用最先进的生物和遗传学方法也无法回答。 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 从心脏瓣膜疾病患者收集的数据；对小鼠的研究表明，这类基因是 对瓣膜结构发育和疾病发病机制具有重要且先前未被认识的贡献者。 这种特定疾病基因及其调节过程的发现在未来具有巨大的潜力 对机械稳定瓣膜组织再生或形成的补救或治疗见解 对瓣膜性心脏病患者有益。