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小泡来源的microRNAs(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 它的相关条件，在美国印第安人(AIS)。拟议的研究是对正在进行的R01的补充 即研究表位转录RNA修饰N6-甲基腺苷作为AS- 来自同一队列中的AIS诱导的T2 DM。多样性补充的候选人是一名 哥伦比亚大学环境健康科学系二年级博士后研究员 大学精密环境健康实验室。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的夏威夷原住民博士后。贯穿始终 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，父母R01的PI，和Baccarelli博士，父母R01的共同PI，以及其他 来自领导家长R01研究团队的初级教员Kupsco博士的支持。候选人 负责完成研究项目的拟议目标，包括1)表征 使用下一代RNA与AS暴露和AS代谢相关的循环EV-miRNAs 强心研究(SHS)中AIS中针对小RNA的测序；2)鉴定EV-miRNAs 与T2 DM风险相关的疾病，包括胰岛素抵抗、高血糖和代谢综合征，以及 事件/流行的T2 DM；3)调查EV-miRNAs是否在AS和AS之间的关系中起中介作用 新陈代谢和T2 DM相关结果；以及4)确定连接EV-miRNA信号的生物途径 AS相关的T2 DM与表位转录特征的改变。在整个拟议的研究中， 应聘者将有一个结构化的培训计划，以促进其所需技能的获得 获得K99/R00职业过渡奖的短期目标和作为一名 独立学术研究人员，这方面的经验和培训包括：1)高级计算 基于人口的研究、高维数据和分子流行病学的方法；2)社区- 心脏代谢性疾病的基础和本土健康研究方法；3)为联邦 资助；4)撰写和传播土著健康研究；以及5)在学术生涯中导航 研究。为了促进这些培训目标，应聘者将参加几个正式的培训 通过哥伦比亚大学提供的机会，他将通过参与家长的活动获得经验 R01，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.