The Epitranscriptome as a Novel Mechanism of Arsenic-Induced Diabetes.

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Project Summary The primary goal of this research project is to investigate extracellular vesicle-derived microRNAs (EV- miRNAs) as a potential mechanistic biomarker of arsenic (As)-associated type 2 diabetes mellitus (T2DM), and its related conditions, in American Indians (AIs). The proposed research is a supplement to an ongoing R01 that is investigating the epitranscriptomic RNA modification N6-methyladenosine as a mechanism of As- induced T2DM from AIs participating in the same cohort. The candidate for the diversity supplement is a second year postdoctoral researcher in the Department of Environmental Health Sciences at Columbia University in the Laboratory of Precision Environmental Health. The candidate is of Native Hawaiian descent, and is to our knowledge, the only Native Hawaiian at the postdoctoral level at Columbia University. Throughout the proposed research and career development training, he will have a strong mentorship team composed of co-mentors Dr. Navas-Acien, PI of the parent R01, and Dr. Baccarelli, co-PI of the parent R01, with additional support from a junior faculty member leading the research team of the parent R01, Dr. Kupsco. The candidate is responsible for the completion of the proposed aims of the research project, including 1) characterizing circulating EV-miRNAs that are associated with As exposure and As metabolism using next-generation RNA sequencing targeted to small RNAs in AIs enrolled in the Strong Heart Study (SHS); 2) identify EV-miRNAs that associate with T2DM risk, including insulin resistance, hyperglycemia, and metabolic syndrome, as well as incident/prevalent T2DM; 3) investigate whether EV-miRNAs mediate the relationship between As and As metabolism, and T2DM-related outcomes; and 4) identify biological pathways linking EV-miRNA signatures of As-associated T2DM with changes in epitranscriptomic signatures. Throughout the proposed research, the candidate will have a structured training plan that will facilitate the acquisition of skillsets necessary for his short-term goal of acquiring a K99/R00 career transition award and his long-term career goal as an independent academic researcher, this experience and training include, 1) advanced computational approaches for population-based research, high-dimensional data, and molecular epidemiology; 2) community- based and Indigenous health research approaches for cardiometabolic diseases; 3) grant writing for federal funding; 4) authoring and communicating Indigenous Health Research; and 5) navigating a career in academic research. To facilitate these training goals, the candidate will be involved in several formal training opportunities offered through Columbia University, he will garner experience through involvement on the parent R01, and he will meet weekly with members of his mentorship team.