Exploratory Analysis of the Functional Implications of MicroRNAs Associated with Incident Type 2 Diabetes and Related Risk Factors.

与 2 型糖尿病事件及相关危险因素相关的 MicroRNA 功能意义的探索性分析。

• 批准号: 10404815
• 负责人: Elena Flowers
• 金额: $ 4.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-02 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404815
• 关键词: Adult; Behavior; Biological; Biological Markers; Biomedical Research; Blood; Blood Glucose; Characteristics; Clinical; Clinical Research; Collection; Complex; Conduct Clinical Trials; Cross-Sectional Studies; Data; Development; Disease; Environment; Environmental Risk Factor; Etiology; Fasting; Funding; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Impairment; Incidence; Individual; Intervention; Knowledge; Life Style; Longitudinal Studies; Measures; Medicine; Metformin; MicroRNAs; Minority Groups; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Overweight; Parents; Participant; Pathway interactions; Pharmacology; Placebos; Plasma; Public Health; Randomized Clinical Trials; Risk; Risk Factors; Risk Reduction; Sampling; Scientist; Specimen; Subgroup; Testing; Time; Training; Underrepresented Minority; United States; United States National Institutes of Health; Weight; arm; career; circulating microRNA; cohort; cost; diabetes prevention program; extracellular; group intervention; improved; insight; inter-individual variation; lifestyle factors; lifestyle intervention; novel marker; novel strategies; novel therapeutics; parent project; phenotypic data; precision medicine; predicting response; predictive marker; prevent; response; risk prediction; treatment arm; treatment optimization

Type 2 diabetes is priority for both public health and precision medicine. The etiology of type 2 diabetes is complex and both genetic and lifestyle/environmental factors contribute to risk. Current approaches to risk prediction and risk reduction are limited because they fail to account for the interactions between biological and lifestyle risk factors. MicroRNAs regulate expression of genes in response to lifestyle factors and capture the combined effects of genetic predisposition and the environment. Extracellular circulating microRNAs, which are readily detectable in blood, are emerging as useful indicators of disease etiology and show changes in response to the environment and behaviors. Prior studies have been primarily cross-sectional in nature and were not powered to evaluate clusters of microRNAs as predictive markers. Our current funded R01 study will determine whether microRNAs predict incident type 2 diabetes and whether there are interactions with risk reduction interventions. We measured microRNAs in a subset of plasma samples banked at the NIDDK biorespository from participants in the completed NIH-funded Diabetes Prevention Program (DPP) trial that tested the effect of metformin, intensive lifestyle intervention, and placebo on risk for type 2 diabetes. This trial showed intensive lifestyle intervention decreased incidence of type 2 diabetes by 58% and metformin by 31% compared to placebo. The existing phenotypic data and biologic specimens from the DPP trial provided an exceptional opportunity to evaluate the relationships between longitudinal changes in both microRNAs and risk for type 2 diabetes in an extremely well characterized sample of individuals who underwent interventions that decreased incidence of type 2 diabetes. The parent study is the first to evaluate, in a large, rigorously conducted clinical trial, microRNAs, singularly and as clusters, as predictors of type 2 diabetes and interactions with risk reduction interventions. This is also the first study to model longitudinal trajectories of microRNAs and fasting blood glucose over time. Building on the parent project, this supplement proposes to identify the genes and biological pathways that are predicted targets of the microRNAs identified in the parent study. The potential impact of the supplement is discovery of the specific mechanisms that may underlie risk for type 2 diabetes within subgroups with future potential for optimization of treatments and discovery of new therapies. This knowledge will improve our understanding of inter-individual variability in risk prediction, optimization of risk reduction interventions, and mechanisms for type 2 diabetes and responses to risk reduction interventions. In addition, this supplement will provide a future scientist from a racially under-represented minority group with training in clinical and biomedical research in order to prepare the candidate for a successful career in academic medicine.

2型糖尿病是公共卫生和精密医学的优先事项。 2型糖尿病的病因是 复杂的以及遗传和生活方式/环境因素都导致风险。当前的风险方法 预测和降低风险是有限的，因为它们无法解释生物学与 生活方式风险因素。 microRNA根据生活方式因素调节基因的表达并捕获 遗传易感性和环境的结合作用。细胞外循环microRNA， 容易在血液中检测到的是疾病病因的有用指标，并显示出反应的变化 对环境和行为。先前的研究主要是横断面的，不是 有动力评估microRNA作为预测标记的簇。我们目前的资助R01研究将确定 microRNA是否预测2型糖尿病的事件以及是否与降低风险相互作用 干预措施。我们测量了在NIDDK Biorespository的血浆样品子集中测量的microRNA 来自已完成的NIH资助糖尿病预防计划（DPP）试验的参与者，该试验测试了 二甲双胍，密集的生活方式干预和安慰剂面临2型糖尿病的风险。该试验显示很密集 与安慰剂相比，生活方式干预措施将2型糖尿病的发病率降低了58％，二甲双胍的发病率降低了31％。 DPP试验中现有的表型数据和生物标本提供了极好的机会 评估microRNA的纵向变化与2型糖尿病风险之间的关系 非常有特点的人的样本，这些人接受了干预措施，以降低发病率的干预措施 2型糖尿病。家长研究是第一个在大型，严格进行的临床试验中评估microRNA的研究。 奇异和作为集群，作为2型糖尿病的预测因子以及与降低风险干预措施的相互作用。这 这也是对随着时间的推移进行模拟microRNA和空腹血糖的纵向轨迹的第一个研究。建筑 在父项目上，该补充提出了识别预测的基因和生物学途径 父母研究中确定的microRNA的靶标。补充的潜在影响是发现 在亚组中可能有2型糖尿病风险的具体机制，其未来可能 优化治疗和发现新疗法。这些知识将提高我们对 风险预测的个体差异，降低风险干预措施的优化和类型的机制 2个糖尿病和对降低风险干预措施的反应。此外，该补充剂将提供未来 来自种族不足的少数群体的科学家，接受了临床和生物医学研究的培训 为了为候选人做好成功的学术医学职业准备。