The role of epigenetic transcriptional memory in monocyte-macrophage cells and cardiovascular disease risk

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Project Summary/Abstract This proposal details a five-year training program to support the candidate to achieve his long-term career goal of building a successful independent transdisciplinary research program featuring clinical, immunology, and epigenetic research to address the impact of epigenetic transcriptional memory in immune cells on cardiovascular disease (CVD) risk in minority populations. The candidate has a strong scientific skillset and knowledge in epigenetics that provides a solid background to ensure his success in pursuing transdisciplinary clinical research focused on CVD. The candidate seeks to focus his career development and enhance his experience and technical research skills in immunology and clinical CVD research. The candidate will acquire essential research skills including flow cytometry, in vitro and ex-vivo monocyte/macrophage functional assays of human cells, and integrative bioinformatics to establish his independence in using his expertise in epigenetics to address CVD. He has already established his own independent research project aimed at defining the role of epigenetic regulation of monocyte/macrophage cellular responses across ethnicities with CVD health disparities. The scientific and institutional environment at the University of Hawaii is well-matched to ensuring the candidate achieves his career goals to study the immune system and CVD. There are multiple independently funded research programs such as the Center for Cardiovascular Disease Research, COBRE Diabetes Center, and Research Multidisciplinary and Translational Research Infrastructure Expansion project that will provide shared resources and core facilities and offer numerous collaborative opportunities in cardiometabolic disease research. A key component of the research career development plan is mentorship from a multi-disciplinary mentoring team focused on cardiovascular disease research consisting of immunology, clinical, and health disparity research experts committed toward contributing their expertise to support the candidate’s career development and expand his research training. The candidate will pursue a hypothesis that dysfunctional monocyte responses associated with high cardiovascular disease risk are related to epigenomic programming differences at inflammatory and metabolic genes and are exacerbated in Native Hawaiians compared to Caucasians. To test this hypothesis, a cross-sectional study of viably cryopreserved blood specimens from 200 Native Hawaiians and age gender research project aimed at addressing the matched Caucasians with clinically defined high and low CVD risk. The specific aims are (1) To measure and compare functional responses of isolated monocyte and macrophage cells from NHOPI and Caucasians with clinically defined low or high CVD risk in the Multiethnic cohort. (2) Determine if epigenetically regulated inflammatory and metabolic genes in isolated monocyte cells from NHOPI and Caucasians associate with CVD risk and differ by ethnicity. (3) Within monocytes from high CVD risk NHOPI and Caucasians, to examine the impact of metformin on the epigenetic state of inflammatory and metabolic genes.