Role of mitophagy in age-related respiratory and vascular diseases

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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.