Mechanistic Insights into The Role of Microtubule Organizing Centers on Cardiomyocyte Structure and Function

微管组织中心对心肌细胞结构和功能作用的机制见解

• 批准号: 10743120
• 负责人: CHARLES C HONG
• 金额: $ 51.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10743120
• 关键词: 1 year old; Architecture; Birth; Cardiac; Cardiac Myocytes; Cell Cycle; Centrioles; Centrosome; Childhood; Cilia; Complex; Congenital Abnormality; Cytoskeleton; Defect; Development; Dilated Cardiomyopathy; Disease; Functional disorder; Genes; Genetic Predisposition to Disease; Heart; Heart Abnormalities; Heart failure; Human; Impairment; Individual; Infant; Intermediate Filaments; Knock-out; Knowledge; Length; Letters; Link; Microcephaly; Microtubule-Organizing Center; Microtubules; Mitochondria; Modeling; Molecular; Mutation; Nuclear; Nuclear Envelope; Pathogenesis; Pathogenicity; Patients; Process; Prognosis; Proteins; Regulation; Reporting; Research; Role; Sarcomeres; Signal Transduction; Structural defect; Structure; Time; causal variant; ciliopathy; drug development; heart function; induced pluripotent stem cell derived cardiomyocytes; infancy; innovation; insight; knock-down; mutant; novel; novel therapeutics; pediatric heart failure; postnatal; proband; programs

Pediatric dilated cardiomyopathy (DCM) has a poor prognosis, particularly for infants <1-year-old, and the drug development efforts have been hampered by the lack of understanding of disease pathophysiology. While the majority of pediatric DCM cases are considered idiopathic, genetic etiologies are commonly suspected. Against this backdrop, we recently identified the RTTN gene, encoding the centrosome protein Rotatin, as a new causal gene for non-syndromic infantile dilated cardiomyopathy (iDCM). Additionally, we found that impaired centrosome reduction, whereby certain centrosome proteins become “re-localized” to the perinuclear region to form perinuclear microtubule organizing center (pnMTOC), underlies the structural and functional defects observed in the mutant cardiomyocytes. While centrosome reduction has been associated with cell cycle exit in the postnatal heart, this represents the first time in which the defective centrosome reduction/pnMTOC assembly has been specifically linked to DCM in humans. Based on these findings we hypothesize that RTTN is a key regulator of centrosome reduction/pnMTOC formation, required for the formation of proper MT cytoskeleton that governs cardiomyocyte structure and function. To better understand the composition and the functional role of pnMTOC important for proper sarcomere architecture during cardiomyocyte maturation, we will utilize the following two specific aims: 1) Determine the centrosome- associated constituents of the pnMTOC in cardiomyocytes and the mechanism that governs their perinuclear localization during cardiac maturation. 2) Determine the mechanisms by which centrosome reduction and/or pnMTOC governs cardiomyocyte structure and function. The proposed research is highly innovative in that it leverages the newly discovered insights into iDCM pathogenesis to better understand the emerging role of the centrosome as a key regulator of cardiomyocyte structure and function. In doing so, this study will define a novel pathogenic mechanism for pediatric heart failure precipitated by impaired cardiomyocyte maturation and open up new therapeutic opportunities for this devastating disease.

儿童扩张型心肌病(DCM)预后很差，尤其是对1岁的婴儿和儿童，而这种药物 由于缺乏对疾病病理生理学的了解，开发工作一直受到阻碍。而当 大多数儿童DCM病例被认为是特发性的，通常怀疑是遗传原因。vbl.反对，反对 在这种背景下，我们最近发现了编码中心体蛋白Rotatin的RTTN基因是一种新的 非综合征婴儿扩张型心肌病(IDCM)的致病基因。此外，我们还发现， 中心体减少，使某些中心体蛋白重新定位到核周区域，以 形成核周微管组织中心(PnMTOC)，是结构和功能缺陷的基础 在突变的心肌细胞中观察到。虽然中心体减少与细胞周期退出有关 在出生后的心脏中，这是第一次有缺陷的中心体减少/pnMTOC 在人类中，组装已经与扩张型心肌病特异性地联系在一起。基于这些发现，我们假设 RTTN是中心体还原/pnMTOC形成的关键调节因子，是形成 适当的MT细胞骨架，调节心肌细胞的结构和功能。为了更好地理解 PnMTOC的组成和功能对正常的肌节构筑至关重要 为了使心肌细胞成熟，我们将利用以下两个特定的目标：1)确定中心体- 心肌细胞pnMTOC的相关成分及其核周调控机制 心脏成熟过程中的定位。2)确定中心体减少和/或 PnMTOC调控心肌细胞的结构和功能。拟议的研究具有很高的创新性，因为它 利用对iDCM发病机制的新发现的见解，更好地理解 中心体作为心肌细胞结构和功能的关键调节因子。通过这样做，这项研究将定义一个 心肌细胞受损引发儿童心力衰竭的新发病机制 成熟并为这一毁灭性疾病开辟新的治疗机会。