Caveolae, T-type Calcium Channels and Cardiac Hypertrophy

描述（由申请人提供）：心脏肥大是预测心血管疾病和死亡率的主要风险因素，约10%的普通人群存在心脏肥大。心肌肥大使个体易于心律失常、心力衰竭和猝死。心脏肥大与结构、电和机械功能障碍有关，这些功能障碍是由细胞内Ca2+水平持续升高引起的，导致这种疾病期间的心律失常和心力衰竭。 在成人心脏中，在心肌细胞水平，Ca2+信号传导和收缩是通过激活L型Ca2+通道启动的。然而，病理性肥大Ca 2+信号的诱导是由胎儿T型Ca 2+通道（TTCC）的重新表达和激活引起的。但是，心肌肥厚中Ca2+信号改变的机制尚不清楚。Caveolae含有支架蛋白Caveolin-3（Cav-3），其组织多蛋白信号复合物并提供心肌细胞内Ca 2+的时间/空间调节。我们的初步数据表明，心脏TTCC定位于小窝，并与小窝蛋白3和调节其功能的心室肌细胞。因此，Caveolae和Caveolin-3可以通过在心肌肥厚期间对心脏TTCC的功能调节来影响Ca2+信号传导。这项建议将针对以下具体目标：1）确定心脏肥大的影响，特别是亚细胞重塑，2）确定Caveolin-3在心肌肥厚过程中对TTCC亚型的调节和独特信号通路的差异调节中的作用3）确定Caveolin-3的功能作用-3和小窝在病理性心脏肥大的发展这项工作的长期目标是确定新的信号机制，在心脏肥大的心脏保护。我们的研究将从心肌细胞到整个动物的水平来确定Caveolae和Cav-3在心脏保护中的作用。从这项工作中获得的见解将有显着的影响，发展的病理性肥大和心力衰竭患者的治疗方式。 公共卫生相关性：心脏病是美国的主要死亡原因，估计每3例死亡中就有1例。心肌肥厚是心肌梗死、心力衰竭、猝死等多种心脏病的主要危险因素。在心脏中发现的某些蛋白质，如小窝蛋白和Ca2+通道，控制心脏收缩功能，并可在肥大期间提供保护。我们在这项研究中的目标是确定新的信号传导机制，并发现参与预防病理性心脏肥大的关键蛋白质，以便设计有效的疾病预防治疗方法。

DESCRIPTION (provided by applicant): Cardiac hypertrophy is a major risk factor predictive of cardiovascular diseases and mortality and exists in about 10% of the general population. Myocardial hypertrophy predisposes individuals to arrhythmia, heart failure and sudden death. Cardiac hypertrophy is associated with structural, electrical, and mechanical dysfunctions resulting from persistent increase in the intracellular Ca2+ levels leading to arrhythmia and heart failure during this disease. In the adult heart at the cardiomyocyte level, Ca2+ signaling and contraction are initiated by the activation of L-type Ca2+ channels. However, the induction of pathological hypertrophic Ca2+ signaling results from the re-expression and activation of fetal T-type Ca2+ channels (TTCC). But, the mechanism of altered Ca2+ signaling in cardiac hypertrophy is not known. Caveolae containing scaffolding protein caveolin-3 (Cav-3) organize multi-protein signaling complexes and provide temporal/spatial regulation of intracellular Ca2+ in cardiomyocytes. Our preliminary data show that the cardiac TTCCs are localized to caveolae and associate with caveolin-3 and regulate their function in the ventricular myocytes. Thus caveolae and caveolin-3 could impact the Ca2+ signaling through functional regulation of cardiac TTCCs during cardiac hypertrophy. This proposal will address the following specific aims: 1) Determine the impact of cardiac hypertrophy, specifically sub cellular remodeling, on the alteration of caveolar macromolecular signaling proteins and regulation Ca2+ signaling through TTCCs 2) Determine the role of caveolin-3 in modulation of TTCC isoforms and differential regulation of unique signaling pathways during cardiac hypertrophy 3) Define the functional role of caveolin-3 and caveolae in the development of pathological cardiac hypertrophy The long-term goal of this work is to identify novel signaling mechanisms relevant to cardiac protection during cardiac hypertrophy. Our studies will define the role of caveolae and Cav-3 in cardiac protection from the level of the cardiac myocyte to the whole animal. The insights gained from this work will have significant implications for development of therapeutic modalities in patients with pathological hypertrophy and heart failure. PUBLIC HEALTH RELEVANC: Heart disease is the leading cause of death in the United States with an estimated 1 of every 3 deaths. Cardiac hypertrophy is a major risk factor predictive of several types' cardiac diseases including, myocardial infarction, heart failure and sudden death. Certain proteins such as caveolins and Ca2+ channels found in the heart control the cardiac contractile function and could offer protection during hypertrophy. Our goal in this study is to identify novel signaling mechanisms and discover key proteins involved in protection against pathological cardiac hypertrophy so effective therapies for disease prevention can be designed.