The Role of SECTM1 in Monocyte Biology and Atherosclerosis

PROJECT SUMMARY /ABSTRACT This proposal details a comprehensive training program for a mentored career development award in functional genomics and systems biology and its application to cardiovascular disease. The applicant seeks to use proteomics and human genetics to provide novel insight into the pathophysiology of atherosclerosis that can be tested, mechanistically in small animal models. The candidate is an Instructor of Medicine at Harvard Medical School and the Director of Cardiovascular Genetics at Beth Israel Deaconess Medical Center. The outlined proposal builds on the candidate’s strong background in bioinformatics following his Master of Biomedical Informatics from Harvard Medical School, to new areas of expertise: computational genomics and small animal model systems. The candidate’s mentor is a renowned expert in molecular profiling using omic technologies and retro-translating novel findings back to the bench in small animal models of disease. The candidate’s scientific advisory committee has a distinguished track record of mentorship and extensive expertise in monocyte biology, murine models of atherosclerosis, human genetics and bioinformatics. The proposed research builds on preliminary studies showing an association of SECTM1, a poorly studied protein with proposed chemokine activity for monocytes and regulator of macrophage phagocytosis, with the development of coronary heart disease in the Jackson Heart Study using proteomic profiling. The applicant now proposes to test the hypothesis that SECTM1 is novel regulator of monocyte biology and contributes to atherosclerosis formation using a murine model of disease. In Aim 1, the applicant will determine the effect of SECTM1a on the proliferation of monocyte progenitors in the bone marrow and its associated pathways. In Aim 2, the applicant will assess the effect of SECTM1a on atherosclerosis lesion formation in mouse models. In Aim 3, the applicant will test the causal association of SECTM1 with other circulating proteins using Mendelian randomization studies to inform new biology of SECTM1-related pathways in humans and will provide a springboard for future mechanistic studies in small animal models. Coronary heart disease remains the leading cause of mortality worldwide, despite the substantial advancements in our understanding of disease pathways and preventative treatments. A large body of evidence has implicated inflammation as a key contributor to the residual burden of disease, with monocytes being important mediators of these processes. The proposal aims to use functional genomics and a systems biology approach towards delineating novel inflammatory pathways towards development of atherosclerosis that has the potential for new targets for preventative treatments for coronary heart disease.