权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic Markers of Short- and Long- Term Near-Normoglycemia Remission in Patients with Ketosis-Prone Diabetes

酮症倾向糖尿病患者短期和长期血糖接近正常缓解的表观遗传标志物

基本信息

批准号：
10450891
负责人：
Priyathama Vellanki
金额：
$ 7.43万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-16 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450891
关键词：
Achievement Advisory Committees Affect African American Antidiabetic Drugs Autoantibodies Beta Cell Biopsy Blood Cell physiology Clinical Clinical Investigator Computational Biology DNA DNA Methylation Data Data Analyses Defect Deterioration Development Plans Diabetes Mellitus Diabetic Ketoacidosis Disease remission Epigenetic Process Exhibits Funding Future Gene Expression Genes Genetic Genetic Transcription Genome Glucagon Glucose Glucose tolerance test Glycosylated hemoglobin A Hand Hour Human Hyperglycemia Immunologics Impairment Institution Insulin Insulin Resistance Insulin Signaling Pathway Insulin-Dependent Diabetes Mellitus Islets of Langerhans Lead Low Prevalence Maintenance Measures Mediating Mentors Mentorship Metabolic Methylation Muscle Newly Diagnosed Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Oral Pancreas Pathway interactions Patients Performance Peripheral Pharmaceutical Preparations Phenotype Play Procedures RNA Recovery Recurrence Relapse Research Resolution Resources Role Sampling Science Site Skeletal Muscle Structure Structure of beta Cell of islet Testing Time Training United States National Institutes of Health Universities base blood-based biomarker career development clinical predictors clinical translation differential expression epigenetic marker experience follow-up glucose uptake improved in vivo insight insulin secretion insulin sensitivity insulin signaling peripheral blood recruit trait transcription factor vastus lateralis

项目摘要

Project Summary/Abstract Ketosis-prone diabetes mellitus (KPDM) affects ~20-50% of African American patients with newly diagnosed diabetes who present with diabetic ketoacidosis (DKA). At presentation of DKA, these patients have a severe decompensation in insulin secretion (beta-cell function) accompanied by severe insulin resistance. Unlike patients with type 1 diabetes, following intensive insulin treatment, many of these patients exhibit improvements in insulin secretion and insulin sensitivity and are able to discontinue insulin therapy (near- normoglycemia remission, HbA1c < 7%). The period of near-normoglycemia remission is variable and many patients eventually experience a hyperglycemic relapse or even DKA. Therefore, studying the underlying mechanisms leading to changes in insulin secretion and sensitivity and near-normoglycemia remission has implications for a significant number of African American patients with diabetes. DNA methylation and gene expression, have been proposed as mechanisms that affect insulin secretion and insulin sensitivity. In this proposal, based on preliminary results, the PI Priyathama Vellanki, MD, will test whether longitudinal gene expression and DNA methylation changes in specific pathways affect quantitative traits of insulin sensitivity and secretion along with achievement and maintenance of near-normoglycemia remission. In Aim1, she will characterize whether gene expression and DNA methylation changes in glucose sensing and insulin secretion pathways associate with quantitative measures of insulin secretion derived from glucagon stimulation tests. In Aim 2, she will characterize glucose uptake and insulin signaling pathways with quantitative traits of insulin sensitivity from frequently-sampled IV glucose tolerance tests (FSIVGTT). She will also test whether gene expression and methylation in these pathways associate with short- and long-term near-normoglycemia remission. Further, in order to develop blood-based biomarkers, she will test whether gene expression and DNA methylation in muscle correlate with those in blood. Successful completion of these aims will yield important insights into mechanisms that underlie changes in insulin sensitivity and secretion through the clinical course of patients with KPDM. The proposed aims will be performed under the guidance of an expert interdisciplinary mentorship team led by her lead mentor Dr. Umpierrez (expertise in KPDM) and co-mentor Dr. Alicia K. Smith (expert in epigenetics) along with an advisory committee comprised of experts in statistical genetics (Dr. Karen Conneely) and computational biology (Dr. Darko Stefanovski). Emory University is a world-class institution that has adequate and ample resources necessary to carry out the research aims, including the Georgia Clinical and Translation Science Alliance. Her structured training plan has formal didactic training at Emory along with hand-on training in performance of phenotyping studies and data analyses. The proposal along with the structured career development plan will poise Dr. Vellanki to become a successful independent NIH-funded clinical investigator.

项目概要/摘要酮症倾向糖尿病 (KPDM) 影响约 20-50% 的非裔美国新诊断患者患有糖尿病酮症酸中毒（DKA）的糖尿病患者。在出现 DKA 时，这些患者患有严重的胰岛素分泌失代偿（β细胞功能）伴有严重的胰岛素抵抗。不像 1 型糖尿病患者在接受强化胰岛素治疗后，其中许多患者表现出改善胰岛素分泌和胰岛素敏感性，并能够停止胰岛素治疗（近- 血糖正常缓解，HbA1c < 7%）。接近正常血糖缓解的时间是可变的，并且许多患者最终会出现高血糖复发，甚至 DKA。因此，研究底层导致胰岛素分泌和敏感性变化以及接近正常血糖缓解的机制对大量非洲裔美国糖尿病患者的影响。 DNA 甲基化和基因表达已被认为是影响胰岛素分泌和胰岛素敏感性。在本提案中，根据初步结果，PI Priyathama Vellanki（医学博士）将测试特定途径中的纵向基因表达和 DNA 甲基化变化是否影响定量胰岛素敏感性和分泌的特征以及接近正常血糖的实现和维持缓解。在 Aim1 中，她将表征葡萄糖中基因表达和 DNA 甲基化是否发生变化传感和胰岛素分泌途径与源自胰岛素分泌的定量测量相关胰高血糖素刺激试验。在目标 2 中，她将描述葡萄糖摄取和胰岛素信号通路的特征来自频繁采样的静脉葡萄糖耐量试验（FSIVGTT）的胰岛素敏感性的定量特征。她会还测试这些途径中的基因表达和甲基化是否与短期和长期相关接近正常血糖的缓解。此外，为了开发基于血液的生物标志物，她将测试是否肌肉中的基因表达和 DNA 甲基化与血液中的相关。顺利完成这些目标将对胰岛素敏感性和分泌变化的机制产生重要的见解通过 KPDM 患者的临床病程。拟议的目标将在由专家领导的跨学科指导团队的指导下实现她的首席导师 Umpierrez 博士（KPDM 专家）和共同导师 Alicia K. Smith 博士（表观遗传学专家）以及由统计遗传学专家（Karen Conneely 博士）组成的咨询委员会以及计算生物学（Darko Stefanovski 博士）。埃默里大学是一所世界一流的大学，拥有充足的资源以及实现研究目标所需的充足资源，包括佐治亚临床和翻译科学联盟。她的结构化培训计划包括在埃默里大学进行的正式教学培训以及实践培训表型研究和数据分析的表现。该提案以及结构化的职业生涯开发计划将使 Vellanki 博士成为一名成功的、由 NIH 资助的独立临床研究者。