Developmental and Biomechanical Mechanisms of Valve Tissue Formation

项目摘要 基于PI实验室在遗传和细胞方面的发现，该提案侧重于新的机制 对于心脏瓣膜的形成至关重要。提案中提出的初步数据显示， DCHS 1基因引起非常常见心脏瓣膜疾病（即，二尖瓣脱垂），并可能由 瓣膜组织在发育过程中如何形成的错误。因此，分子、细胞和生物工程 将利用这些方法来测试关于DCHS 1在瓣膜开发过程中如何发挥作用的特定假设。 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，回答有关心脏的生物物理学问题- 迄今为止，即使使用最先进的生物学技术也无法解决瓣膜疾病， 基因方法。了解导致瓣膜病的发育发病机制 在COBRE的过程中，这种疾病将使我们能够与其他目标教员融合在一起（Jean-Soo博士 Lee [项目：治疗性纳米颗粒递送]，A. Simionescu [项目：干细胞和无细胞支架]） 使PI的研究朝着病变瓣膜组织再生的方向发展。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，并促进与核心设施和目标教师在这个COBRE的互动。 二尖瓣脱垂（MVP）影响全世界每40个人中就有1个。定义为二尖瓣瓣叶翻卷， 在左心房，它是需要手术修复的孤立二尖瓣返流的最常见原因。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。的 拟议的工作利用了以前从MVP患者中收集的未识别的遗传数据; 小鼠的研究表明，这类基因是一个重要的和以前未被认识到的贡献者瓣膜结构 发育、瓣膜生物力学特性和疾病发病机制。这个特殊的发现 疾病基因及其调控的过程对未来的治疗或治疗见解具有巨大的潜力 有利于MVP患者的机械稳定瓣膜组织的再生或形成。

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.