TRPC Channel Regulation of Cardiac Hypertrophy and Contractility

心肌梗死（MI）是美国死亡和发病的主要原因。 的患者 患有MI（心脏病发作）的患者通常会出院， 血液动力学曲线，但与他们的心脏（梗塞区）的死部分。在那里发生了一次心肌梗死后 是心脏的主要结构和功能重塑， 心脏收缩性能差，最终导致充血性心力衰竭（HF）。小说 减少MI后结构和功能重塑的治疗将减少HF。最近 研究表明，心脏不同部位的钙调节异常， 称为微结构域的肌细胞引起肌细胞结构和功能的异常。在 特别是，有证据表明，诱导病理性重塑和 收缩障碍发生在独特的“信号”和“兴奋-收缩偶联”中， 微区包含一类了解甚少的典型瞬时受体电位 （TRPC）渠道。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性差有关。本项目谋求 降低心肌梗死后TRPC通道活性，改善心肌结构和功能。的 具体的目的是：1）确定TRPC通道如何与LTCC和其他Ca ~（2+）相互作用， 在单独的信号传导和EC偶联微结构域中的调节蛋白， 心脏病中的病理性肥大和收缩力降低。2)更好地 通过定义新的TRPC-LTCC配偶体来表征微结构域信号传导，以及3） 确定MI后TRPC活性的抑制（在MI后显性阴性（dn）TRPC的表达）是否 转基因小鼠，并开始在猪中用AAV 6-dnTRPC进行翻译研究）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通道功能亢进可改善心脏结构和功能。的项目 从基础发现科学到在大型动物中测试新疗法 具有基本人类特征的模型。

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.