Cilia and Valvular Heart Disease

项目总结 基于PI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。提案中提供的数据是一种演变 我们在第一轮资助中公布的研究结果表明，DZIP1基因的突变会导致非常 常见的心脏瓣膜疾病(即二尖瓣脱垂)，可由瓣膜组织形成的错误引起 在开发过程中。这些发现导致了一种新的概念，即纤毛参与瓣膜的发育。 虽然DZIP1的功能是我们在本提案中研究的重点，但我们也将通过以下方式定义新的机制 心脏瓣膜建立三板层ECM组织，以及这种组织如何反馈给细胞 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，到目前为止，即使使用最新的- 艺术、生物学和遗传方法。 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识别的基因数据。 收集自心脏瓣膜病患者；在老鼠身上的研究表明，这类基因是一种重要的 以及以前未被认识的瓣膜结构发育和疾病发病机制的贡献者。这个 这种特殊疾病基因及其调控过程的发现为未来的治疗提供了巨大的潜力。 或对机械稳定的瓣膜组织再生或形成的治疗洞察力将是有益的 给心脏瓣膜病患者。

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.