Caveolae, T-type Calcium Channels and Cardiac Hypertrophy

描述(申请人提供)：心肌肥厚是心血管疾病和死亡率的主要危险因素，存在于大约10%的普通人群中。心肌肥厚易导致心律失常、心力衰竭和猝死。心肌肥厚与结构、电和机械功能障碍有关，这些功能障碍是由于细胞内钙离子水平持续升高而导致的，导致心律失常和心力衰竭。在成人心脏中，在心肌细胞水平上，钙信号和收缩是由L型钙通道激活而启动的。然而，病理性肥大钙信号的诱导是胎儿T型钙通道(TTCC)重新表达和激活的结果。但是，心肌肥厚时钙信号改变的机制尚不清楚。含有支架蛋白小窝蛋白-3(Cav-3)的小窝组织多蛋白信号复合体，为心肌细胞内钙离子提供时间/空间调节。我们的初步数据表明，心脏TTCCs定位于小窝，并与小窝-3相关，并调节其在心室肌细胞中的功能。因此，小窝和小窝蛋白-3可能通过对心肌肥厚时心肌TTCC的功能调节来影响钙信号转导。这项建议将针对以下具体目标：1)确定心肌肥厚，特别是亚细胞重塑，对TTCCs中腔泡大分子信号蛋白变化的影响和对钙信号的调节；2)确定小窝蛋白-3在心肌肥厚过程中调节TTCC亚型和独特信号通路的差异性调节中的作用；3)确定小窝蛋白-3和小窝蛋白在病理性心肌肥厚发生发展中的功能作用本工作的长期目标是确定与心肌肥厚过程中的心脏保护相关的新的信号机制。我们的研究将从心肌细胞水平到整个动物确定小窝和Cav-3在心脏保护中的作用。从这项工作中获得的见解将对发展病理性肥厚和心力衰竭患者的治疗方式具有重要意义。 公共卫生报告：心脏病是美国的主要死因，估计每3人中就有1人死于心脏病。心肌肥厚是预测心肌梗死、心力衰竭和猝死等多种心脏疾病的主要危险因素。心脏中发现的某些蛋白质，如小窝蛋白和钙离子通道，控制着心脏的收缩功能，并在肥厚期间提供保护。我们在这项研究中的目标是识别新的信号机制，并发现参与保护病理性心肌肥大的关键蛋白，以便设计有效的疾病预防疗法。

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.