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TRPC Channel Regulation of Cardiac Hypertrophy and Contractility

TRPC 通道对心脏肥大和收缩力的调节

基本信息

批准号：
8916819
负责人：
Steven R Houser
金额：
$ 27.14万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916819
关键词：
Adult Angiotensin II Animal Model Apoptotic Arrhythmia Calcium Calcium Signaling Cardiac Cardiac Myocytes Cations Caveolae Cell Death Cessation of life Complex Confocal Microscopy Congestive Congestive Heart Failure Contracts Coupling Cyclic GMP Depressed mood Disease Dominant-Negative Mutation Endothelin-1 Family Felidae Family suidae Functional disorder Goals Health Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Hospitals Housing Human Characteristics Hypertension Hypertrophy Immunoprecipitation Knowledge Lead Link Mass Spectrum Analysis Mediating Membrane Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Necrosis Neonatal Pathologic Patients Peptides Performance Phenotype Phosphorylation Play Proteins Pump Regulation Research Risk Role Science Signal Transduction Source Staging Stress Structure System TRP channel Testing Therapeutic Tissues Transgenic Mice Translations Ventricular Ventricular Remodeling Yeasts base caveolin-3 clinical application genetic regulatory protein hemodynamics improved loss of function mortality novel novel strategies novel therapeutics prevent receptor response screening translational study yeast two hybrid system

项目摘要

Myocardial infarction (MI) is a major cause of mortality and morbidly in the US. Patients that have suffered an MI (heart attack) are usually released from the hospital with a stable hemodynamic profile but with a dead portion of their heart (the infarct zone). After an MI there are major structural and functional remodeling of the heart that ultimately produce a dilated heart with poor contractile performance, culminating in congestive heart failure (HF). Novel therapies that reduce post MI structural and functional remodeling would reduce HF. Recent studies suggest that abnormalities in calcium (Ca) regulation within different portion of cardiac myocytes, termed microdomains, cause abnormalities in myocyte structure and function. In particular, there is evidence that the Ca signaling that induces pathological remodeling and contractile disturbances occurs within unique "signaling" and "excitation-contraction coupling" microdomains that contain a poorly understood class of canonical transient receptor potential (TRPC) channels. TRPC channel expression and activity are increased after MI and their activity has been linked to pathological hypertrophy and poor contractility. This project seeks to reduce excess TRPC channels activity to improve cardiac structure and function after MI. The Specific Aims are: 1) To determine how TRPC channels interact with LTCCs and other Ca regulatory proteins within separate signaling and EC coupling microdomains to cause pathological hypertrophy and depressed contractility in cardiac disease. 2) To better characterize microdomain signaling by defining novel TRPC-LTCC partners, and 3) To determine if inhibition of TRPC activity after MI (expression of a dominant negative (dn) TRPC in transgenic mice and to begin translational studies with AAV6-dnTRPC in pigs) improves cardiac structure and function. This research will develop novel approaches to determine if reducing excess TRPC channel function after MI can improve cardiac structure and function. The projects build from fundamental discovery science to testing of novel therapeutics in a large animal model with essential human characteristics.

在美国，心肌梗死(MI)是导致死亡和死亡的主要原因.患者患有心肌梗塞(心脏病发作)的人通常出院时病情稳定血流动力学特征，但有心脏的死亡部分(梗死区)。在那里经历了一次MI之后是心脏的主要结构和功能重塑，最终导致心脏扩张心脏收缩性能差，最终导致充血性心力衰竭(HF)。小说减少心肌梗死后结构和功能重构的治疗将减少心衰。近期研究表明，心脏不同部位的钙调节异常肌细胞，被称为微域，导致心肌细胞结构和功能的异常。在……里面特别是，有证据表明，诱导病理性重塑和收缩干扰发生在独特的“信号”和“兴奋-收缩耦合”中。包含一类鲜为人知的典型瞬时受体潜力的微域 (TRPC)通道。心肌梗死后TRPC通道表达和活性增加活动与病理性肥大和收缩能力差有关。这一项目旨在减少过量的TRPC通道活动，改善心肌梗死后的心脏结构和功能。这个具体目标是：1)确定TRPC渠道如何与LTCC和其他案例交互调节蛋白在单独的信号和EC偶联微域内引起心脏疾病中的病理性肥厚和收缩能力降低。2)做得更好通过定义新的TRPC-LTCC伙伴来表征微域信号，以及3) 确定心肌梗死后TRPC活性是否受到抑制(显性阴性(DN)TRPC在转基因小鼠并开始在猪中进行AAV6-dnTRPC的翻译研究)改善心脏结构和功能。这项研究将开发新的方法来确定是否减少心肌梗死后TRPC通道功能过剩可改善心脏结构和功能。这些项目从基础发现科学到在大型动物身上测试新疗法具有人类本质特征的模特。