Friday, May 9, 2025
5/9/2025
Inflammation-mediated platelet hyperreactivity and thrombosis - Project Summary/Abstract The Candidate is an assistant professor in pediatrics and a young physician-scientist dedicated to developing an academic career focused on investigating the intersection of inflammation and thrombosis through the study of the mechanisms by which inflammation promotes platelet hyperreactivity. With a strong background in inflammation, megakaryocyte, and platelet biology, the candidate looks to develop new expertise in autophagy and metabolism to determine their contribution to platelet hyperreactivity and thrombosis. The Career Development Plan described in the proposal outlines 2 years of mentored training, including technical skill training and career development activities, to promote the successful transition to independence and future funding. The Candidate’s Mentors and Co-Mentors have proven track-records of excellent translational research productivity and successful mentorship. The Research Plan: Inflammation contributes to the development of cardiovascular disease (CVD) and promotes platelet hyperreactivity and thrombosis in older humans (aging) and patients with rheumatoid arthritis (RA). The thrombotic events experienced by these groups are characterized by platelet-rich arterial clots denoting that platelet hyperreactivity is central for the elevated morbidity and mortality in these populations. The central hypothesis of this application is that chronic inflammation promotes platelet hyperreactivity and thrombosis through the reprogramming of key platelet metabolic pathways. The work proposed in this application is set to elucidate the mechanisms by which chronic inflammation promotes platelet hyperreactivity through dysregulation of critical metabolic regulators of platelet function such as autophagy (aim 1) and the pentose phosphate pathway (PPP, [aim 2]) in older humans and in patients with rheumatoid arthritis (aim3). For this purpose, I have integrated multidisciplinary mentoring and advisory teams of world-known experts in autophagy (Andrew Thorburn, Ph.D.), metabolomics (Angelo D’Alessandro Ph.D.), and platelet biology (Matthew Rondina, MD) to guide the successful completion of the proposed work. The mentoring, skills, and tools developed throughout the K99 phase of this award will lay down a solid foundation to establish my independent research program focused on the study of the platelet metabolic determinants for hyperreactivity and thrombosis. Finally, and most important, discoveries from our research have the potential to improve the care and outcomes not only for older individuals and patients with RA but also children with chronic inflammatory conditions such as Juvenile Idiopathic Arthritis (JIA) and sickle cell disease.
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