Role of mitophagy in age-related respiratory and vascular diseases

线粒体自噬在年龄相关呼吸和血管疾病中的作用

• 批准号: 10541147
• 负责人: Daniel Robert Goldstein
• 金额: $ 58.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541147
• 关键词: Abdominal Aortic Aneurysm; Age; Aging; Aortic Aneurysm; Atherosclerosis; Award; Cardiovascular Diseases; Chronic; Data; Development; Disease; Elderly; Goals; Host Defense; Human; Hypertension; Immune response; Immunologic Receptors; Impairment; Inflammation; Influenza; Knowledge; Laboratories; Lung diseases; Lung infections; Michigan; Mitochondria; Mitochondrial DNA; Mus; Natural Immunity; Organ Transplantation; Pathogenesis; Pathway interactions; Persons; Physicians; Physiological Processes; Proteins; Publications; Reporter; Research; Respiratory Disease; Role; Scientist; Seminal; Toll-like receptors; Transgenic Mice; Translating; Universities; Vascular Diseases; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; age related; antiviral immunity; atherogenesis; biobank; improved outcome; influenza infection; influenzavirus; novel; novel therapeutics; organ transplant rejection; programs; vascular inflammation

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.

项目概要/摘要 我的研究计划的首要主题是了解先天免疫如何增强年龄- 相关的心血管和肺部疾病。作为一名医学科学家，我研究了先天的 对不同疾病的免疫力长达20年。在对 Toll-like 的作用做出了几项开创性的发现之后 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知识 对与年龄相关的疾病的研究具有免疫力。我的实验室取得了多项突破性的发现 炎症如何在衰老过程中促进疾病，特别是： i) 全身性病毒感染； ii) 流感肺 感染; iii) 血管疾病； iv) 器官移植排斥。我们这项提案的中心主题是 线粒体自噬（一种清除受损线粒体的生理过程）的改变支撑着线粒体的传播 流感肺部感染和血管疾病的进展。我们假设流感病毒传播期间 感染病毒“劫持”线粒体自噬，增强病毒传播，降低抗病毒免疫力，进一步削弱 主机防御。在慢性血管炎症期间，我们假设受损的线粒体自噬导致 线粒体DNA的积累，激活先天免疫，促进疾病，例如 动脉粥样硬化、高血压和腹主动脉瘤（AAA）。根据我们之前的出版物和 新颖的初步数据表明，我们将在该提案中追求两大目标。第一个目标将阐明 使用新型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有条件地删除。在我们的第二个目标中，我们将使用我们的新型小鼠 阐明线粒体自噬的动态及其在动脉粥样硬化、高血压和 AAA 过程中的需求 发展。在这两个目标中，我们将利用密歇根大学的关键生物样本库来转化我们的 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，我们的研究项目有潜力开发新的疗法 改善呼吸道病毒感染和血管疾病的结果，特别是老年人。