Regulation of Cardiac Myocyte Differentiation

心肌细胞分化的调节

基本信息

批准号：
8786091
负责人：
David M BADER
金额：
$ 38.48万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-09-30 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786091
关键词：
Ablation Adult Anthracyclines Antineoplastic Agents Automobile Driving Biological Biology Cancer Patient Cardiac Cardiac Myocytes Cardiac development Cardiomyopathies Cardiovascular Diseases Cell physiology Cells Complex Congenital Heart Defects Coupling DNA Data Data Set Defect Development Dilated Cardiomyopathy Disease Disease Outcome Disease Progression Drug usage ERBB2 gene Elderly Embryo Etiology Event Failure Family Fibrosis Foundations Functional disorder Genes Genetic Models Goals Growth Health Heart Heart Block Heart Diseases Human Hypertrophy Intervention Lead Microtubule Stabilization Microtubule-Associated Proteins Microtubules Minor Modeling Molecular Monitor Morphogenesis Movement Mus Muscle Cells Mutation Nature Neonatal Onset of illness Organism Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Physiological Plant Roots Play Population Positioning Attribute Process Property Proteins Publishing RNA chemical synthesis Reaction Reagent Regulation Reporting Risk Role Series Severity of illness Shapes Structure Sudden Death Testing Time TimeLine Topoisomerase II Trastuzumab Vesicle Transport Pathway Woman Work cardiogenesis clinically relevant disorder risk drug testing enzyme activity heart function human disease inhibitor/antagonist loss of function mature animal neonate novel prevent young adult

项目摘要

DESCRIPTION (provided by applicant): We now understand that CENP-F is a powerful regulator of microtubule (MT) function that controls diverse cell functions. Loss of CENP-F function in the early embryo results in minor changes in cardiac morphogenesis but fully penetrant, late adult-onset dilated cardiomyopathy (DCM). This was the first report demonstrating that disruption of any MT-associated protein causes heart disease, thus setting a novel but long predicted paradigm. Further, identification of a human family with a CENP-F mutation leading to multiple defects including the heart increases the significance of our work. Importantly, we have now discovered that loss of CENP-F function results in a hyper-stabilized MT network that is at increased risk with intervention of chemotherapeutics targeting MT function. Indeed, these drugs cause DCM in a significant subset of human cancer patients. These paradigm-setting data, our genetic models, and collective expertise uniquely position us to make ground-breaking and clinically relevant advances impacting human health. We have two integrated and major goals. Our first goal is to determine the precise role(s) of CENP-F and the MT network in specific events during cardiac development and how their loss of function subsequently leads to heart disease. These studies are essential for a mechanistic understanding of CENP-F function in development and in the etiology of DCM. Knowing that loss of CENP-F function hyper-stabilizes the MT network, a second independent yet interactive goal is to determine whether "MT fragile" hearts are at increased risk with chemotherapeutics: 1. only from a second hit directed specifically at MTs, 2. at even greater risk from a broader hit attacking MTs and other targets, and/or 3. at generalized risk from an "off target" hit that does not attack MTs. Thus, the proposed studies will provide a fundamental understanding of CENP-F/MT function in cardiogenesis and lead to concrete advances in the analysis of cardiovascular disease caused by chemotherapeutic intervention.

描述（由申请人提供）：我们现在了解CENP-F是控制多种细胞功能的微管（MT）功能的强大调节剂。早期胚胎中CENP-F功能的丧失会导致心脏形态发生的略有变化，但完全渗透性，晚期成人发作的心肌病（DCM）。这是第一个报告表明，任何与MT相关蛋白的破坏会导致心脏病，从而产生一种新颖但长期预测的范式。此外，鉴定具有CENP-F突变的人类家庭，导致包括心脏在内的多种缺陷增加了我们工作的重要性。重要的是，我们现在发现，CENP-F功能的损失导致了一个超稳定的MT网络，该网络的风险增加，而靶向MT功能的化学治疗剂的干预。实际上，这些药物在大量人类癌症患者中引起DCM。这些范式设定的数据，我们的遗传模型以及集体专业知识独特地为我们定位，以实现影响人类健康的开创性和临床相关的进步。我们有两个集成和主要目标。我们的第一个目标是确定CENP-F和MT网络在心脏发育过程中的特定事件中的确切作用，以及其功能丧失如何导致心脏病。这些研究对于对开发和DCM病因中CENP-F功能的机械理解至关重要。知道CENP-F功能的丧失使MT网络过度稳定，第二个独立但互动的目标是确定“ MT脆弱”的心脏是否对化学治疗学的风险增加了风险：1。仅从第二个命中率指向MTS的第二次命中率是MTS，2。更大的风险甚至更大的风险更大，从更广泛的命中攻击的MTS和其他目标和3个攻击的风险。因此，拟议的研究将在心脏病中提供对CENP-F/MT功能的基本理解，并在化学治疗干预引起的心血管疾病分析中带来具体的进步。