Neutrophil Mitophagy in Antiphospholipid Syndrome

About This Grant

PROJECT SUMMARY / ABSTRACT Antiphospholipid syndrome (APS) is an immunothrombotic disease that is characterized by recurrent thrombosis and pregnancy losses. Current management hinges on chronic anticoagulation. However, anticoagulation is ineffective in approximately 20% of patients with APS and does not adequately treat the potentially fatal microangiopathic features of APS. Thus, there is a critical need to develop a better understanding of disease mechanisms to advance therapies in APS. Neutrophils are implicated in the pathophysiology of APS and metabolism plays an important role in guiding physiologic and pathologic neutrophil functions. The overall goal in this proposal is to evaluate how dysfunctional mitochondrial autophagy (mitophagy) alters neutrophil metabolism to promote pathogenic neutrophil extracellular trap release in APS. This project will play a crucial role in helping the candidate achieve his long-term career goals, which include: (1) to achieve expertise in the metabolism of inflammatory diseases, (2) to become an established and well- funded principal investigator, and (3) to develop into a trusted mentor and advisor for future trainees. These goals will be accomplished by incorporating a strong mentorship environment and a formal instructional plan. Mentorship Environment: The candidate is an Assistant Professor in the Divisions of Rheumatology and Pediatric Rheumatology at the University of Michigan, with 75% protected time for research. He has received mentorship from Dr. Jason Knight in APS pathogenesis and from Dr. Costas Lyssiotis in cellular metabolism. With this proposal, he is seeking support to expand his research into investigating dysfunctional neutrophil mitophagy as a mediator of APS pathogenesis. To support this project and his career development, the candidate has assembled a strong team of mentors, who are experts in their respective fields. Formal instruction: The scientific goals for this proposal include: (1) to build skills to assess mitochondrial function and mitophagy in humans and mice, (2) to develop a deeper understanding of cellular metabolism, and (3) acquire proficiency in disease-relevant mouse models. These will complement the following career development goals: (1) to develop the leadership, team building, and mentoring skills needed to manage a translational research team, (2) to improve oral and written communication skills in support of disseminating research and obtaining independent grants, and (3) to engage with a community of scientists to become a trusted citizen of the rheumatology field. These goals will be accomplished through a combination of formal didactic instruction, mentorship, and laboratory-based experimentation. Research: The specific aims for this proposal are to: (1) characterize the derangements in mitophagy and the subsequent impact on mitochondrial function and metabolism in APS patient neutrophils, and (2) define mechanisms by which neutrophil mitophagy modulates metabolism, NETosis, and thrombosis in APS.