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: 10322449
• 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 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322449
• 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 Diseases; age related; antiviral immunity; atherogenesis; base; 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.

项目摘要/摘要 我的研究计划的总体主题是了解先天免疫如何提高年龄 - 作为物理科学家，我已经调查了先天性 不同疾病的免疫力已有20年。在对Toll样的角色做出了几秒钟的发现之后 受体（TLR），关键的先天免疫受体，在器官移植中，我应用了先天知识 对与年龄相关疾病的研究的免疫力。我的实验室已经对 炎症如何促进衰老期间的疾病：i）全身病毒感染； ii）影响力肺 感染; iii）血管疾病；和iv）器官移植排斥。我们在此提案中的中心主题是 线粒体的改变是去除线粒体受损的物理过程，是基于扩散的基础 流感肺部感染和血管疾病的进展。我们假设在影响力病毒期间 感染病毒“劫持”线粒体以增强病毒蔓延，降低抗病毒免疫力并进一步弱 主持人防御。在慢性血管炎症期间，我们假设线粒体受损会导致 线粒体DNA的积累，该DNA激活先天免疫学以促进疾病，例如 动脉粥样硬化，高血压和腹主动脉瘤（AAA）。根据我们以前的出版物和 新颖的初步数据，我们将在该提案中实现两个广泛的目标。第一个目标将阐明 使用新型线索记者小鼠和转基因小鼠在影响者Genza病毒感染期间的线粒体感染期间 关键的线粒体蛋白已被有条件地删除。在我们的第二个目标中，我们将使用新颖的老鼠 在动脉粥样硬化，高血压和AAA期间阐明线粒体的动力学及其需求 发展。在这两个目标中，我们都将利用密歇根大学的关键生物局体来翻译我们的 对人类的发现。这种奖励机制将使我们能够揭示线粒体影响的新颖途径 影响和血管疾病，例如动脉粥样硬化和AAA。通过将我们的发现转化为 人类在这个奖项的过程中，我们的研究计划有可能开发出新颖的疗法 改善呼吸道病毒感染和血管疾病的结局，特别是在较早的情况下。