Protection of the Aged Myocardium

描述（申请人提供）：随着美国人口老龄化，预计到2035年，老年人（>65岁）将从13-14%增加到25%。如果这一趋势继续下去，未来50年内，超过50%的美国人口和超过20亿的全球人口将“老龄化”。老年人的健康面临着巨大的挑战，因为衰老与无数疾病有关。心血管疾病是美国发病率和死亡率的主要原因，其中>50%的死亡归因于冠状动脉疾病，并且>80%的这些死亡发生在65岁及以上的人中。老年心脏比年轻心脏对缺血性损伤更敏感。已经提出了几种理论来解释这种老化缺陷。这些理论要么援引了遗传学、生物化学、分解代谢或生理学的成分。虽然缺血耐受性中与年龄相关的缺陷的机制尚不清楚，但它们可能涉及细胞信号传导和线粒体的异常，这些异常是遗传、生化、分解代谢和生理缺陷的综合结果。针对这些机制的治疗有可能挽救老年心肌。我们的初步研究表明，小窝蛋白是本地化的motoprotea和可以调节线粒体功能/动力学。我们提出了以下假设：1）小窝蛋白的靶向细胞运输到关键的调控接头（即，肌膜和线粒体）是对缺血应激的关键反应; 2）由于膜定位的小窝蛋白的损失，在衰老心肌中小窝蛋白向线粒体的细胞运输被破坏; 3）在衰老动物中通过膜和线粒体靶向在不同细胞区室中恢复小窝蛋白可以提供恢复对心肌缺血耐受性的手段。具体目标1：确定膜定位小窝蛋白的缺失是否导致小窝蛋白表达/小窝形成的缺失，从而限制小窝蛋白向线粒体的运输，以及老化心肌中小窝蛋白的膜靶向表达是否恢复向线粒体的运输。具体目标2：确定老化是否导致线粒体定位的小窝蛋白减少以改变线粒体功能（即，活性氧物质的产生和mPTP的调节）和线粒体动力学（即，融合-分裂以调节线粒体周转和线粒体自噬），并且如果靶向线粒体的小窝蛋白表达对于恢复线粒体功能/动力学是必要的和足够的。具体目标3：确定在膜或线粒体中靶向表达小窝蛋白是否是恢复老年心脏缺血耐受的必要和充分条件。

DESCRIPTION (provided by applicant): With the aging of the United States population, it is estimated that the elderly (>65 years of age) will increase from 13-14% to 25% by 2035. If this trend continues, >50% of the United States population and >2 billion people worldwide will be "aged" in the next 50 years. Aged individuals face formidable challenges to their health, as aging is associated with a myriad of diseases. Cardiovascular disease is the leading cause of morbidity and mortality in the United States with >50% of mortality attributed to coronary artery disease and >80% of these deaths occurring in those age 65 and older. Aged hearts are more sensitive than young hearts to ischemic insults. Several theories have been proposed to account for this aging deficit. These theories either invoke a genetic, a biochemical, a catabolic, or a physiologic component. Though the mechanisms that underlie an age-related deficit in ischemic tolerance are not clear, they likely involve abnormalities in cellular signaling and mitochondria that are a combined result of genetic, biochemical, catabolic, and physiologic deficiencies. Therapeutics that target these mechanisms have potential to rescue the aged myocardium. Our preliminary studies show that caveolin is localized to motochondria and can modulate mitochondrial function/dynamics. We propose the following hypotheses: 1) targeted cellular trafficking of caveolin to key regulatory junctions (i.e., sarcolemmal membrane and mitochondria) is a critical response to ischemic stress; 2) cellular trafficking of caveolin to mitochondria is disrupted in the aged myocardium due to loss of membrane-localized caveolin; 3) restoration of caveolin in distinct cellular compartments via membrane and mitochondrial targeting in aged animals may provide a means to restore tolerance to myocardial ischemia. The following specific objectives will be addressed: Specific Aim 1: Determine if loss of membrane-localized caveolin leads to loss of caveolin expression/caveolae formation thus limiting trafficking of caveolin to mitochondria and if membrane-targeted expression of caveolin in aged myocardium restores trafficking to mitochondria. Specific Aim 2: Determine if aging results in reduced mitochondria-localized caveolin to alter mitochondrial function (i.e., reactive oxygen species generation and regulation of mPTP) and mitochondrial dynamics (i.e., fusion-fission to regulate mitochondrial turnover and mitophagy) and if mitochondria-targeted caveolin expression is necessary and sufficient to restore mitochondrial function/dynamics. Specific Aim 3: Determine if targeted expression of caveolin in membrane or mitochondria is necessary and sufficient to restore ischemic tolerance in aged hearts.