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，老年人口(65岁)将从13-14%增加到25%。如果这一趋势继续下去，在接下来的50年里，50%的美国人口和20亿全球人口将“老龄化”。老年人的健康面临着严峻的挑战，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%的死亡是由冠状动脉疾病引起的，80%的死亡发生在65岁及以上的人群中。老年人的心脏比年轻的心脏对缺血侮辱更敏感。已经提出了几种理论来解释这种老龄化的赤字。这些理论要么引用遗传成分、生化成分、分解代谢成分，要么引用生理成分。尽管与年龄相关的缺血耐受缺陷的机制尚不清楚，但它们可能涉及细胞信号和线粒体的异常，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方法有可能挽救老化的心肌。我们的初步研究表明，小窝蛋白定位于线粒体，并可以调节线粒体的功能/动力学。我们提出以下假设：1)靶向细胞转运小窝蛋白到关键的调节连接(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丢失，老年心肌中小窝蛋白到线粒体的细胞运输被破坏；3)在老年动物中，通过膜和线粒体靶向恢复不同细胞间隔中的小窝蛋白可能为恢复对心肌缺血的耐受提供一种手段。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/小窝形成的丧失，从而限制小窝蛋白向线粒体的转运，以及在老年心肌中膜靶向表达小窝蛋白是否能恢复向线粒体的运输。具体目标2：确定衰老是否导致线粒体局部小窝蛋白减少，从而改变线粒体功能(即，活性氧的产生和MPTP的调节)和线粒体动力学(即，融合-裂变调节线粒体周转和有丝分裂)，以及线粒体靶向小窝蛋白表达是否必要和充分，以恢复线粒体功能/动力学。具体目标3：确定膜或线粒体靶向表达小窝蛋白是否是恢复老年心脏缺血耐受的必要条件和充分条件。

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.