Aging, Viral Immunity and Atherosclerosis

描述(由申请人提供)：临床研究表明，衰老会增加动脉粥样硬化的风险。随着老年人数量的持续增长，老年人动脉粥样硬化的发病率将给我们的卫生保健资源带来沉重的负担。越来越多的人认识到炎症是动脉粥样硬化发展的关键病理生理学机制。重要的是，实验和临床研究都提供了证据，表明包括病毒在内的微生物感染会加剧动脉粥样硬化的发展。先前的研究表明，衰老会损害免疫功能，导致清除病毒的能力降低。来自我们实验室的数据，在最近获得的R01(R01AG028082)的支持下，已经证明衰老损害了血浆细胞样树突状细胞(PDC)的功能，pDC是病毒感染的关键先天传感器。这一K02应用将补充目前资助的R01，并将研究衰老如何加速动脉粥样硬化过程；特别是，它将阐明病毒感染随着年龄增长而加剧动脉粥样硬化的机制。重要的是，我们将研究基于TLR的疫苗是否能预防随年龄增长的后续病毒感染和改善病毒加重的动脉粥样硬化。在测试这些假说时，我们将与两位资深血管生物学家Sessa博士和Tellides博士合作。因此，K02计划将使我能够专注于我的研究计划，并发展新的科学合作，这将有助于领导未来关于衰老对心血管疾病的影响的计划项目。相关性(见说明)：我们社会中的老年人数量将继续增长。由于老年人患心脏病和中风的可能性增加，了解衰老是如何导致心血管疾病增加的将是当务之急。这项提议将使用小鼠实验模型来研究衰老导致心血管疾病的机制。

DESCRIPTION (provided by applicant): Clinical Studies have demonstrated that aging increases the risk of atherosclerosis. As the number of older people continues to grow, morbidity from atherosclerosis in older adults will pose a heavy burden on our health care resources. There has been a growing appreciation that inflammation is a key pathopysiological mechanism that underpins the development of atherosclerosis. Importantly, both experimental and clinical studies provide evidence that microbial infections, including viruses, exacerbate the development of atherosclerosis. Prior studies have demonstrated that aging impairs immune function and leads to a reduced ability to clear viruses. Data from our laboratory, supported by a recently acquired R01 (R01AG028082), has demonstrated that aging impairs the function of plasmacytoid DCs (pDCs), critical innate sensors of viral infection. This K02 application will complement the currently funded R01 and will examine how aging accelerates the atherosclerotic process; in particular, it will elucidate the mechanisms by which viral infections exacerbate atherosclerosis with aging. Importantly, we will examine if TLR-based vaccines protect against subsequent viral infection with aging and ameliorate virus-exacerbated atherosclerosis. In testing these hypotheses, we will collaborate with two senior vascular biologists, Drs. Sessa and Tellides. Thus, this K02 proposal will allow me to focus on my research program and develop new scientific collaborations that will be instrumental to leading a future program project on the effects of aging on cardiovascular diseases. Relevance (see instructions): The number of older people in our society will continue to grow. As older people will have an increased probability of developing heart attacks and strokes, it will be imperative to understand how aging leads to increased cardiovascular diseases. This proposal will investigate mechanisms by which aging leads to cardiovascular diseases using murine experimental models.