Developmental and Biomechanical Mechanisms of Valve Tissue Formation

瓣膜组织形成的发育和生物力学机制

• 批准号: 9279166
• 负责人: Russell Norris
• 金额: $ 9.5万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9279166
• 关键词: Affect; Arrhythmia; Biocompatible Materials; Biological; Biomechanics; Biomedical Engineering; Biophysics; Cardiac Death; Cell Polarity; Cell surface; Cells; Centers of Research Excellence; Clinical; Collaborations; Congestive Heart Failure; Core Facility; Data; Development; Developmental Process; Disease; Endocarditis; Equipment; Etiology; Faculty; Family; Future; Gene Mutation; Genes; Genetic; Growth; Heart Atrium; Heart Diseases; Heart Valve Diseases; Heart Valves; Histologic; Human; Image; Imaging Device; In Vitro; Individual; Inherited; Lead; Left atrial structure; Life; Mechanics; Mediating; Membrane; Mentors; Microtubules; Mitral Valve Insufficiency; Mitral Valve Prolapse; Modality; Molecular; Molecular Analysis; Morphogenesis; Mus; Mutation; Natural regeneration; Operative Surgical Procedures; Pathogenesis; Patients; Process; Property; Proteins; Ptosis; Randomized; Resources; Role; Schedule; Secondary to; Services; Shapes; Stem cells; Sudden Death; Testing; Therapeutic; Thinking; Time; Tissues; Work; base; bioimaging; cardiogenesis; genetic approach; human disease; in vivo; insight; interstitial cell; mechanical properties; meetings; mouse model; nanoparticle; novel; planar cell polarity; prevent; protein E; repaired; scaffold; tool

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.

项目概要 该提案基于 PI 实验室的遗传和细胞发现，重点关注新机制 这对于心脏瓣膜的形成至关重要。该提案中提供的初步数据表明，突变 DCHS1 基因导致一种非常常见的心脏瓣膜疾病（即二尖瓣脱垂），可能由以下原因引起 发育过程中瓣膜组织形成的错误。因此，分子、细胞和生物工程 这些方法将用于测试有关 DCHS1 在瓣膜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以及细胞、组织、 和分子分析核心）将提供独特的机会来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和技术也无法解决瓣膜疾病。 遗传方法。了解有助于瓣膜的发育发病机制 疾病将使我们能够在 COBRE 课程期间与其他目标教师融合（Dr. Jeoung Soo） Lee [项目：治疗性纳米粒子递送]、A. Simionescu 博士 [项目：干细胞和无细胞支架]) 将 PI 的研究发展到病变瓣膜组织的再生。此外，科学（罗杰博士 Markwald）和临床导师（John Ikonimidis 博士）将通过以下方式加速 PI 的发现： 定期安排会议并促进与 COBRE 核心设施和目标教员的互动。 全球每 40 个人中就有 1 人受到二尖瓣脱垂 (MVP) 的影响。定义为二尖瓣小叶滚滚进入 左心房，它是需要手术修复的孤立性二尖瓣关闭不全的最常见原因。它是 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 拟议的工作利用了从 MVP 患者收集的先前未被识别的遗传数据；研究于 小鼠表明，这类基因是瓣膜结构的重要且以前未被认识的贡献者 发育、瓣膜生物力学特性和疾病发病机制。这一特殊事件的揭开 疾病基因及其调节过程对于未来的治疗或治疗洞察具有巨大的潜力 再生或形成机械稳定的瓣膜组织，这将有利于 MVP 患者。