TRPC Channel Regulation of Cardiac Hypertrophy and Contractility

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。

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.