Role of mitophagy in age-related respiratory and vascular diseases

项目总结/摘要 我的研究项目的首要主题是了解先天免疫如何增加年龄- 相关的心血管和肺部疾病。作为一名医学科学家，我研究了先天性的 20年来对不同疾病的免疫力。在对Toll样蛋白的作用进行了几项开创性的发现后， 受体（TLR），关键的先天免疫受体，在器官移植中，我应用了我的先天免疫学知识， 对与年龄有关的疾病的研究的免疫力。我的实验室有几个突破性的发现， 炎症如何促进衰老过程中的疾病，特别是：i）全身性病毒感染; ii）流感肺 感染; iii）血管疾病;和iv）器官移植排斥。我们在这一建议中的中心主题是， 线粒体自噬的改变，一种去除受损线粒体的生理过程， 流感肺部感染和血管疾病的进展。我们假设在流感病毒感染期间 感染病毒"劫持"线粒体自噬，以加强病毒传播，降低抗病毒免疫力，并进一步削弱 宿主防御在慢性血管炎症期间，我们假设受损的线粒体自噬导致了 线粒体DNA的积累，激活先天免疫，促进疾病，如 动脉粥样硬化、高血压和腹主动脉瘤（AAA）。根据我们以前的出版物和 新的初步数据，我们将追求两个广泛的目标，在这个建议。第一个目标将阐明 使用新的线粒体自噬报告小鼠和转基因小鼠在流感病毒感染期间进行线粒体自噬，其中 关键的线粒体自噬蛋白已被条件性删除。在我们的第二个目标中，我们将使用我们的新型小鼠， 阐明动脉粥样硬化、高血压和AAA期间线粒体自噬的动力学及其需求 发展在这两个目标中，我们将利用密歇根大学的关键生物储存库， 人类的发现。这种奖励机制将使我们能够揭示线粒体自噬影响的新途径 流感感染和血管疾病，如动脉粥样硬化和AAA。通过将我们的发现转化为 在这个奖项的过程中，我们的研究计划有潜力开发新的疗法， 改善呼吸道病毒感染和血管疾病的预后，特别是老年人。

PROJECT SUMMARY/ABSTRACT The overarching theme of my research program is to understand how innate immunity enhances age- associated cardiovascular and pulmonary diseases. As a physician scientist, I have investigated innate immunity in different diseases for 20 years. After making several seminal findings on the role of Toll-like receptors (TLRs), key innate immune receptors, in organ transplantation, I applied my knowledge of innate immunity to the studies of age-related diseases. My laboratory has made several groundbreaking findings as to how inflammation promotes diseases during aging, specifically: i) systemic viral infections; ii) influenza lung infection; iii) vascular diseases; and iv) organ transplant rejection. Our central theme in this proposal is that alterations in mitophagy, a physiological process to remove damaged mitochondria, underpins the spread of influenza lung infection and the progression of vascular diseases. We hypothesize that during influenza viral infection the virus “hijacks” mitophagy to enhance viral spread, reduce anti-viral immunity and further weaken host defense. During chronic vascular inflammation, we hypothesize that impaired mitophagy leads to the accumulation of mitochondrial DNA, which activates innate immunity to promote diseases, such as atherosclerosis, hypertension and abdominal aortic aneurysms (AAA). Based on our prior publications and novel preliminary data, we will pursue two broad goals in this proposal. The first goal will elucidate the role of mitophagy during influenza viral infection using novel mitophagy reporter mice and transgenic mice in which key mitophagy proteins have been conditionally deleted. In our second goal, we will use our novel mice to elucidate the dynamics of mitophagy and its requirement during atherosclerosis, hypertension and then AAA development. In both goals, we will leverage key biorepositories at The University of Michigan to translate our findings to humans. This award mechanism will allow us to reveal novel pathways by which mitophagy impacts both influenza infection and vascular diseases, such as atherogenesis and AAA. By translating our findings to humans over the course of this award, our research program has the potential to develop novel therapies to improve the outcomes of respiratory viral infections and vascular diseases, particularly in the elderly.