Cilia and Valvular Heart Disease

项目摘要 基于PI实验室及其合作者在遗传和细胞方面的发现，该提案侧重于 新的机制是心脏瓣膜形成的关键。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，DZIP 1基因的突变会导致非常严重的 常见的心脏瓣膜疾病（即，二尖瓣脱垂），并且可能由瓣膜组织如何形成的错误引起 在发展过程中。这些发现导致了纤毛参与瓣膜发育的新概念。 虽然DZIP 1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： 心脏瓣膜建立了一个三层ECM组织，以及它如何反馈给细胞， 抑制瓣膜特定区域的纤毛发生。我们的研究将提供独特的机会来回答 关于心脏瓣膜疾病的问题，迄今为止，即使是用最新的技术也无法回答， 艺术生物学和遗传学方法。 心脏瓣膜病是一种严重的临床问题，影响5-7%的人口。其并发症 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- 这类疾病的外科治疗。这项拟议中的工作利用了以前未被承认的基因数据 从心脏瓣膜疾病患者中收集;在小鼠中的研究表明，这类基因是一个重要的 以及以前未认识到的对瓣膜结构发育和疾病发病机制的贡献。的 揭示这种特殊的疾病基因及其调控过程对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 心脏瓣膜病患者。

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.