Circulating MicroRNAs and Hyperglycemia

循环 MicroRNA 和高血糖

• 批准号: 9324971
• 负责人: Pandora Luke Januszewski
• 金额: $ 16.18万
• 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/9324971
• 关键词: Adipose tissue; Advisory Committees; Algorithms; American; Amputation; Animals; Asian Americans; Award; Biological; Biological Markers; Blindness; 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; Genetic Transcription; 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; Testing; Theoretical model; Time; Tissues; Translations; Universities; Untranslated RNA; Visceral; Washington; angiogenesis; arm; base; blood glucose regulation; chemokine; circulating biomarkers; circulating microRNA; clinical translation; cohort; cost; design; diabetes risk; differential expression; egg; experimental study; follow-up; glucose metabolism; high risk; improved; in vivo; insulin receptor substrate 1 protein; lipid biosynthesis; loss of function; miRNA expression profiling; mortality; novel; predictive marker; prospective; public health relevance; study population; 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)：潘多拉·旺德博士是华盛顿大学的普通内科医生和心血管疾病流行病学家，她的目标是在糖尿病临床研究中确立自己的独立研究员地位。这个为期五年的项目的重点是表观遗传学，这是转化型糖尿病研究中一个重要的新兴领域，因为它有望成为预测性生物标记物和潜在干预措施的来源。资金将支持旺德博士实现三个目标：(1)在普通人群和高危人群中加深对高血糖和胰岛素抵抗(H&IR)表观遗传机制的了解；(2)学习适用于表观遗传学研究和数据分析的先进方法；以及(3)完成一个集实验室、临床和人群水平调查于一体的转化型表观遗传学研究项目。她建立了一个指导团队和咨询委员会，成员包括内科医生、流行病学家、一名实验室医学医生和一名生物统计学家，他们在研究和指导方面有着良好的记录。高血糖和胰岛素抵抗(H&IR)会导致相当大的发病率和死亡率。过多的内脏脂肪组织(VAT)是发生H&IR的重要危险因素。然而，增值税积累导致胰岛素抵抗的机制仍然不清楚，因此针对这一联系的治疗一直受到限制。目前检测葡萄糖代谢早期变化的方法既昂贵又耗时。符合这些变化的新的循环生物标志物可以提供糖尿病发病机制的信息，并有助于早期发现。MicroRNAs是基因表达的转录后调节因子，参与糖代谢的重要细胞功能，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。这个应用的假设是循环 在VAT中差异表达的miRNAs(包括let-7、miR-103/-107、miR-126、miR-144和miR-181)的水平与H&IR的发生有关。这一假设将通过一项有三个方面的研究来验证：一项针对健康美国人队列的横断面研究，以及两项针对糖尿病高危人群(亚裔美国人和孕妇)的病例对照研究。主要目的是：测试(1)在健康的美国人群中，循环中与增值税相关的炎症性miRNAs水平是否与更大的胰岛素抵抗相关；(2)在亚裔美国人群中，炎症性血浆中的炎症性VAT miRNAs水平与10年后更高的葡萄糖耐受性相关；以及(3)妊娠早期的炎症性增值税水平与妊娠期糖尿病的更高发病率相关。在电子计算机/活体实验中的后续行动将确定已识别的miRNAs的特征，并促进结果的翻译。识别与事件H&IR相关的miRNAs将促进对糖尿病发病机制的了解，改善早期发现，并促进旨在预防的新干预措施。