Circulating MicroRNAs and Hyperglycemia

循环 MicroRNA 和高血糖

• 批准号: 8963142
• 负责人: Pandora Luke Januszewski
• 金额: $ 14.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963142
• 关键词: Adipose tissue; Advisory Committees; Algorithms; American; Amputation; Asian Americans; Award; Biological; Biological Markers; Blood; Blood Circulation; Blood Glucose; Cardiovascular Diseases; Case-Control Studies; Cell physiology; Child; Clinical; Communities; Computer Simulation; Cross-Sectional Studies; Data Analyses; Data Set; Development; Diabetes Mellitus; Diabetes prevention; Disease; Early Diagnosis; Enrollment; Epidemiologist; Epigenetic Process; Face; Funding; Gene Expression; General Population; Gestational Diabetes; Glucose Intolerance; Goals; Human; Hyperglycemia; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Internist; Intervention; Investigation; Japanese American; Kidney Failure; Learning; Ligands; Link; Lower Extremity; Measures; Medicine; Mentors; Mentorship; Metabolism; Methods; MicroRNAs; Modeling; Morbidity - disease rate; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Perinatal; Physicians; Plasma; Population; Population Study; Pregnancy; Pregnant Women; Prevention; Records; Regulator Genes; Research; Research Personnel; Research Project Grants; Risk Factors; Source; Staging; Testing; Theoretical model; Time; Tissues; Translations; Universities; Untranslated RNA; Visceral; Washington; angiogenesis; arm; base; blood glucose regulation; chemokine; circulating microRNA; cohort; cost; design; diabetes risk; differential expression; egg; follow-up; glucose metabolism; high risk; improved; in vivo; insulin receptor substrate 1 protein; lipid biosynthesis; loss of function; mortality; novel; prospective; public health relevance; research study; targeted treatment

 DESCRIPTION (provided by applicant): This is an application for a K08 award for Dr. Pandora Wander, a general internist and cardiovascular disease epidemiologist at the University of Washington, who aims to establish herself as an independent investigator in clinical diabetes research. The focus of the five-year project is epigenetics, an important emerging domain in translational diabetes research, for its promise as a source of both predictive biomarkers and potential interventions. Funds would support Dr. Wander in the attainment of three goals: (1) developing understanding of epigenetic mechanisms of hyperglycemia and insulin resistance (H&IR) in the general population and in high-risk sub-groups; (2) learning advanced methods appropriate for epigenetic studies and data analyses; and (3) completing a translational epigenetic research project integrating lab-based, clinical, and population-level investigations. She has established a mentorship team and advisory committee comprising internists, epidemiologists, a lab medicine physician, and a biostatistician with strong track records of research and mentoring. Hyperglycemia and insulin resistance (H&IR) cause substantial morbidity and mortality. Excess visceral adipose tissue (VAT) is a strong risk factor for development of H&IR. The mechanisms by which accumulation of VAT leads to insulin resistance remain obscure, however, and therefore therapies targeting this link have been limited. Current methods to detect early changes in glucose metabolism are expensive and time-consuming. Novel circulating biomarkers that coincide with these changes could provide information about diabetes pathogenesis and facilitate early detection. MicroRNAs are post-transcriptional regulators of gene expression that participate in cellular functions important to glucose metabolism including inflammation, adipogenesis, and angiogenesis. They can be measured in tissues and in the circulation. The hypothesis for this application is that circulating levels of miRNAs (including let-7, miR-103/-107, miR-126, miR-144, and miR-181) that are differentially expressed in VAT and upregulate pro-inflammatory targets, are prospectively related to the development of H&IR. This hypothesis will be tested using a study with three arms: a cross-sectional study in a healthy American cohort, and two case-control studies in cohorts at high diabetes risk (Asian Americans and pregnant women). The primary aims are: To test (1) whether levels of circulating inflammatory VAT-related miRNAs are associated with greater insulin resistance in a healthy American population; (2) baseline plasma levels of inflammatory VAT miRNAs are prospectively associated with a higher incidence of glucose intolerance at 10-year follow-up in an Asian-American population; and (3) plasma levels of inflammatory VAT in early pregnancy are associated with a higher incidence of gestational diabetes. Follow-up in silico/in vivo experiments will characterize identified miRNAs and facilitate translation of findings. Identifying miRNAs related to incident H&IR will advance understanding of the pathogenesis of diabetes, improve early detection, and facilitate new interventions aimed at prevention.

 描述（由申请人提供）：这是一份为华盛顿大学的普通内科医生和心血管疾病流行病学家Pandora Wander博士申请K 08奖的申请，她的目标是将自己确立为临床糖尿病研究的独立研究者。这个为期五年的项目的重点是表观遗传学，这是转化糖尿病研究中一个重要的新兴领域，因为它有望成为预测生物标志物和潜在干预措施的来源。资金将支持Wander博士实现三个目标：（1）在普通人群和高风险亚组中发展对高血糖和胰岛素抵抗（H&IR）的表观遗传机制的理解;（2）学习适用于表观遗传研究和数据分析的先进方法;（3）完成整合实验室，临床和人群水平调查的转化表观遗传研究项目。她建立了一个导师团队和咨询委员会，由内科医生，流行病学家，实验室医学医生和生物统计学家组成，具有良好的研究和指导记录。高血压和胰岛素抵抗（H&IR）导致大量的发病率和死亡率。过多的内脏脂肪组织（VAT）是H& IR发展的一个强有力的危险因素。然而，VAT积累导致胰岛素抵抗的机制仍然不清楚，因此针对该环节的治疗受到限制。目前检测葡萄糖代谢早期变化的方法昂贵且耗时。与这些变化相一致的新的循环生物标志物可以提供有关糖尿病发病机制的信息，并促进早期检测。MicroRNA是基因表达的转录后调节因子，其参与对葡萄糖代谢重要的细胞功能，包括炎症、脂肪生成和血管生成。它们可以在组织和循环中测量。这种应用的假设是， mirna的水平在VAT中差异表达并上调促炎靶标的miR-144和miR-181（包括let-7、miR-103/-107、miR-126、miR-144和miR-181）与H& IR的发展前瞻性相关。一项在健康美国人队列中进行的横断面研究，以及两项在糖尿病高危人群（亚裔美国人和孕妇）中进行的病例对照研究。主要目标是：检测（1）在健康美国人群中，循环中的炎性VAT相关miRNA水平是否与更高的胰岛素抵抗相关;（2）在亚裔美国人人群中，炎性VAT miRNA的基线血浆水平与10年随访时葡萄糖耐受不良的发生率较高具有前瞻性相关性;（3）妊娠早期血浆炎症性VAT水平与妊娠期糖尿病的发生率较高相关。后续的计算机模拟/体内实验将表征鉴定的miRNA并促进结果的翻译。鉴定与H&IR事件相关的miRNAs将促进对糖尿病发病机制的理解，改善早期检测，并促进旨在预防的新干预措施。