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

项目摘要 本研究项目的主要目标是研究细胞外囊泡来源的microRNA（EV- miRNAs）作为砷（As）相关的2型糖尿病（T2 DM）的潜在机制生物标志物，以及 美国印第安人（American Indians，AIs）拟议的研究是对正在进行的R 01的补充 该研究正在研究表转录组RNA修饰N6-甲基腺苷作为As- 从参与同一队列的AI中诱导T2 DM。多样性补充的候选人是一个 哥伦比亚环境健康科学系博士后研究员 大学精密环境卫生实验室。候选人是夏威夷原住民后裔， 据我们所知，他是哥伦比亚大学唯一一位博士后的夏威夷土著。在整个 建议的研究和职业发展培训，他将有一个强大的导师团队组成， 共同导师Navas-Acien博士（母公司R 01的PI）和Baccarelli博士（母公司R 01的共同PI），以及其他 支持从一个初级教员领导的研究团队的父母R 01，博士Kupsco。候选 负责完成研究项目的拟议目标，包括1）表征 使用下一代RNA的与As暴露和As代谢相关的循环EV-miRNA 对参加强心研究（SHS）的AI中的小RNA进行靶向测序; 2）鉴定EV-miRNA 与2型糖尿病风险相关，包括胰岛素抵抗、高血糖和代谢综合征，以及 研究EV-miRNAs是否介导AS和AS之间的关系 代谢，和T2 DM相关的结果;和4）确定连接EV-miRNA签名的生物学途径， AS相关T2 DM伴表转录组学特征变化。在整个拟议的研究中， 候选人将有一个结构化的培训计划，这将有助于获得必要的技能， 短期目标是获得K99/R 00职业过渡奖，长期目标是成为 独立的学术研究人员，这种经验和培训包括，1）先进的计算 基于人群的研究方法、高维数据和分子流行病学; 2）社区- 为心脏代谢疾病的基础和土著健康研究方法; 3）为联邦撰写补助金 资助; 4）创作和交流土著健康研究;和5）在学术生涯中导航 research.为了促进这些培训目标，候选人将参与几个正式的培训 通过哥伦比亚大学提供的机会，他将通过参与父母的经验， R 01，他将每周与他的导师团队成员会面。

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.