Developmental and Biomechanical Mechanisms of Valve Tissue Formation

项目摘要 基于PI实验室的基因和细胞发现，这项建议侧重于新的机制 对心脏瓣膜的形成至关重要。提案中提供的初步数据显示， DCHS1基因导致一种非常常见的心脏瓣膜疾病(即二尖瓣脱垂)，并可由 发育过程中瓣膜组织如何形成的错误。因此，分子、细胞和生物工程 这些方法将被用来测试关于DCHS1在阀门开发过程中如何发挥作用的具体假设。 与Cobre核心设施(生物工程和生物成像核心和细胞、组织、 和分子分析核心)将提供独特的机会来回答关于心脏的生物物理问题- 瓣膜疾病，到目前为止，即使使用最先进的生物学和 遗传方法。了解瓣膜形成的发育致病机制 疾病将允许我们在科布雷的过程中与其他目标教员整合(Jeoung Soo博士) Lee[项目：治疗性纳米颗粒传递]，A.Simion escu博士[项目：干细胞和无细胞支架]) 使PI的研究朝着病变瓣膜组织的再生方向发展。此外，科学(罗杰博士 Markwald)和临床(John Ikonimidis博士)导师将通过以下方式加速PI的发现 定期安排会议，并促进与科布雷核心设施和目标教职员工的互动。 二尖瓣脱垂(MVP)在全球范围内每40人中就有1人受到影响。定义为二尖瓣叶滚滚进入 左心房是单纯性二尖瓣返流最常见的原因，需要手术修复。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。这个 拟议的工作利用了从MVP患者那里收集的以前未被识别的基因数据； 小鼠表明，这类基因是瓣膜结构的一个以前未被认识到的重要贡献者 发展，瓣膜生物力学特性和疾病发病机制。揭开这一特殊的面纱 疾病基因及其调控的过程在未来的治疗或治疗方面具有巨大的潜力 促进机械稳定的瓣膜组织的再生或形成，这将有利于MVP患者。

Project Summary Based on genetic and cellular discoveries made in the PI's lab, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Preliminary 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. As such, molecular, cellular, and bioengineering approaches will be utilized to test specific hypotheses on how DCHS1 functions during valve development. Extensive collaborations with the COBRE core facilities (Bioengineering and Bioimaging Core and Cell, Tissue, and Molecular Analysis Core) will provide unique opportunities to answer biophysical questions about heart- valve diseases that heretofore have been impossible to answer using even state-of-the-art biological and genetic approaches. Understanding the developmental pathogenetic mechanisms that contribute to valve disease will allow us, during the course of the COBRE, to integrate with other target faculty (Dr. Jeoung Soo Lee [project: therapeutic nanoparticle delivery], Dr. A. Simionescu [project: stem cells and acellular scaffolds]) to evolve the PI's studies towards regeneration of diseased valve tissue. Additionally, scientific (Dr. Roger Markwald) and clinical (Dr. John Ikonimidis) mentors will serve to accelerate the PI's discoveries through regularly scheduled meetings and facilitate interactions with core facilities and target faculty in this COBRE. Mitral valve prolapse (MVP) affects 1 in 40 individuals worldwide. Defined as billowing of the mitral leaflets into the left atrium, it is the most common cause of isolated mitral regurgitation requiring surgical repair. Its complications include congestive heart failure, endocarditis, atrial arrhythmias, and sudden death. The proposed work capitalizes on previously unrecognized genetic data collected from MVP patients; studies in the mouse show that this class of genes is an important and previously unrecognized contributor to valve structural development, valve biomechanical properties 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 MVP patients.