Dzip1 and Mitral Valve Prolapse

Dzip1 和二尖瓣脱垂

• 批准号: 10171896
• 负责人: Russell Norris
• 金额: $ 49.93万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171896
• 关键词: Affect; Animal Model; Arrhythmia; Biochemical; Biological; Biomechanics; Cardiovascular system; Cilia; Clinical; Complex; Congestive Heart Failure; Data; Defect; Detection; Development; Disease; Docking; Endocarditis; Etiology; Failure; Family; Fibrosis; Foundations; Future; Generations; Genes; Genetic; Genetic Epistasis; Goals; Health; Heart Atrium; Heart Valve Diseases; Heart Valves; Heart failure; Human; Human Genetics; Hyperplasia; Image; In Vitro; Individual; Intervention; Knock-in; Knock-in Mouse; Lead; Lesion; Light; Link; Mechanics; Medical; Membrane; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Molecular; Morbidity - disease rate; Mus; Mutation; Natural regeneration; Nuclear; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Peptides; Phenotype; Population; Population Study; Process; Ptosis; Reporter; Signal Transduction; Structure; Sudden Death; Systole; Techniques; Testing; Therapeutic; Tissues; United States; Validation; Ventricular; Vesicle; Work; base; beta catenin; cardiogenesis; cilium biogenesis; conditional knockout; experimental study; genetic approach; genetic variant; improved; in vivo; induced pluripotent stem cell; insight; kinetosome; mortality; mouse model; novel; novel therapeutics; peptidomimetics; sudden cardiac death; trafficking

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 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. As such, our proposal evaluates how cilia form during development and how DZIP1 functions to regulate both ciliogenesis and/or β-catenin activities during development. 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.

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。提案中提供的数据显示， DZIP 1基因中的突变引起非常常见的心脏瓣膜疾病（即，二尖瓣脱垂），并且可以 这是由于瓣膜组织在发育过程中形成的错误造成的。这些发现引出了一个新的概念 纤毛与瓣膜的发育有关因此，我们的建议评估纤毛如何形成在发展过程中， 以及DZIP 1如何在发育过程中发挥作用以调节纤毛发生和/或β-连环蛋白活性。我们 研究将提供独特的机会来回答迄今为止存在的关于心脏瓣膜疾病的问题， 即使用最先进的生物学和遗传学方法也无法回答。 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。拟议的工作利用了以前未被识别的遗传数据 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。