TITLE: Cellular mechanisms of Mac-1 mediated atheroprotection ABSTRACT Introduction: This proposal outlines a five-year training program to support my transition into an independent pharmacist-scientist, while studying the role of the Mac-1 integrin (CD11b/CD18) in atherosclerosis development and complications. Candidate: I completed a Doctor of Pharmacy degree with honors at Creighton University prior to beginning a postdoctoral fellowship at the University of Miami in May of 2016. During my postdoctoral training, I expanded my expertise to basic and clinical vascular research, publishing 14 manuscripts and three more under review during this period. I was recently promoted to Research Assistant Professor in the Department of Surgery, Miller School of Medicine at the University of Miami. Career development plan: My mentors and I have put together a plan that builds upon my previous training to acquire a diverse set of technical and leadership skills that will enhance my trajectory toward becoming an independent investigator. These include microsurgery, mass cytometry, bone marrow transplantation, and grantsmanship courses. Mentoring committee: I will work with a multidisciplinary team of experts (vascular surgery, vascular biology, immunology, and integrin biology) who will provide mentorship and advice during my transition to independence. My mentors and advisors are recognized investigators in their respective fields with an excellent record of funding, publications, and mentorship. We have agreed that I will publish as senior author since the beginning of my K08 training to speed up my transition to independence. Environment/Institutional support: I have the full commitment of my department, which will ensure laboratory and office space, 95% protected time for research, support personnel, and full access to equipment and shared resources. Research plan: My overall scientific goal is to find better therapies for atherosclerosis and to potentially help regress established plaques. My central hypothesis is that Mac-1 activation decreases atherosclerotic burden by reducing monocyte infiltration and promoting a pro-resolving macrophage phenotype through inhibition of the IL-13 receptor. This hypothesis is built upon strong preliminary data using a pharmacological Mac-1 agonist and a novel knock-in model of Mac-1 activation, with both approaches supporting an atheroprotective role for the Mac-1 receptor. I will test my hypothesis in three specific aims that will determine if Mac-1: 1) controls atherogenesis and monocyte recruitment in early disease, 2) modulates macrophage differentiation in plaques, and 3) promotes inflammation resolution and efflux of macrophages in existing lesions. Expected outcomes: I have the necessary research tools and resources to complete my research plan as outlined in the proposal. I expect to publish at least three top-quality manuscripts during the first three years of my training. I plan to apply for my first R01 in year four and to become a fully funded investigator by the end of the K08?s five-year training period.
Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory condition that affects 10% of the United States adult population, and with serious cardiac and ischemic complications for half of these patients. Anti-hyperlipidemic therapies do not fully address the burden of ASCVD in the population. The research and training proposed in this application are relevant to public health because they increase our understanding of the cellular mechanisms associated with atherosclerosis development, progression, and potential resolution.
