Cilia and Valvular Heart Disease

项目摘要 根据PI的实验室和他的合作者所做的基因和细胞发现，这项建议侧重于 对心脏瓣膜形成至关重要的新机制。提案中提供的数据表明， DCHS1基因的突变会导致一种非常常见的心脏瓣膜疾病(即二尖瓣脱垂)，并可以 是由发育过程中瓣膜组织形成的错误引起的。这些发现导致了 将纤毛确定为瓣膜发育的关键和未开发区域，并是这一提议的基础。 我们的研究将提供独特的机会来回答迄今为止关于心脏瓣膜疾病的问题。 已经不可能用最先进的生物学和遗传学方法来回答。 心脏瓣膜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 外科手术治疗这种疾病的手术疗法。这项拟议的工作利用了以前未被发现的基因 从心脏瓣膜病患者收集的数据；在老鼠身上的研究表明，这类基因是一种 在瓣膜结构发育和疾病发病机制中重要的和以前未被认识的贡献者。 这种特殊的疾病基因及其调控过程的发现具有巨大的未来潜力。 对机械稳定的瓣膜组织再生或形成的治疗性或治疗性洞察力 有益于心脏瓣膜病患者。

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.