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Transcriptional and Post-translational Dysregulation of SERCA in Type 2 Diabetes

2 型糖尿病中 SERCA 的转录和翻译后失调

基本信息

批准号：
8091458
负责人：
Carmella Evans-Molina
金额：
$ 7.62万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8091458
关键词：
ATP2A2 Agonist Architecture Atherosclerosis Attenuated Beta Cell Biochemical Biological Assay Biological Preservation Calcium Cardiac Myocytes Cardiovascular system Cell physiology Cells Chromatin Chronic Co-Immunoprecipitations Complex Couples Data Development Diabetes Mellitus Diabetic mouse Diagnosis Disease Down-Regulation EMSA Employee Strikes Endoplasmic Reticulum Epigenetic Process Euchromatin Exocytosis Exposure to Failure Functional disorder Gene Activation Gene Expression Gene Proteins Genes Genetic Transcription Glucose Histone Code Homeostasis Hyperglycemia Immunoblotting Incidence Inflammatory Insulin Insulin Resistance Islets of Langerhans K-Series Research Career Programs Laboratories Literature Luciferases Maintenance Mass Spectrum Analysis Messenger RNA Metabolic Nitrates Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Organ PPAR gamma Pancreas Pathogenesis Pathologic Pathway interactions Patients Peripheral Pioglitazone Play Post-Translational Protein Processing Post-Translational Regulation Production Prospective Studies Proteins Publishing Pump Regulation Research Role Site Site-Directed Mutagenesis Societies Stress Structure of beta Cell of islet Techniques Testing Time Transactivation Transcriptional Activation Transcriptional Regulation Vascular Smooth Muscle Work blood glucose regulation chromatin immunoprecipitation cofactor cytokine db/db mouse design diabetic endoplasmic reticulum stress histone methyltransferase improved insulin granule insulin secretion islet mouse model nitration oxidation promoter protein expression public health relevance research study treatment strategy voltage

项目摘要

DESCRIPTION (provided by applicant): At the time of diagnosis, a patient with Type 2 Diabetes Mellitus (T2DM) is estimated to have lost nearly 50% of his or her 2 cell function. Moreover, large prospective studies like the UKPDS, demonstrate that islet function declines continuously throughout the course of this disease. The long-range objective of this applicant is to define the biochemical and epigenetic pathways that govern gene expression and cellular function in the pancreatic 2 cell in order to identify key sites of dysregulation in the pathological state of T2DM. Insulin release from the 2 cell occurs through a Ca2+ dependent mechanism that couples cellular depolarization with intracellular Ca2+ influx from voltage-gated Ca2+ channels, and insulin granule exocytosis. The maintenance of intracellular calcium homeostasis is dependent on adequate sarco-endoplasmic reticulum Ca2+ ATPAse (SERCA) gene expression, protein levels, and protein activity. Preliminary and published studies show that islets from diabetic mice manifest striking changes in SERCA mRNA and protein levels. Further, data from the cardiovascular literature suggests that SERCA is highly susceptible to nitration, oxidation, and degradation under inflammatory conditions. The hypothesis underlying this proposal is that the hyperglycemic and cytokine enriched milieu of diabetes leads to dual insults that alter SERCA2 gene expression and protein activity, which have profound downstream effects on islet calcium homeostasis and islet secretory function. To test this hypothesis, two specific aims are proposed. In Aim 1, the transcriptional regulation of the SERCA2 gene in Type 2 diabetes will be characterized. Experiments will be performed to identify transcriptional cofactors for SERCA2 gene transactivation and to define the epigenetic pathways that govern SERCA2 expression in the islet. In Aim 2, the post-translational regulation of SERCA2 activity in T2DM will be systematically characterized through experiments designed to correlate the development of irreversible inactivating post- translational modifications of SERCA2 protein with endoplasmic reticulum Ca2+ levels and islet secretory function. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus is a disorder of glucose homeostasis caused by a combination of insulin resistance and progressive dysfunction of the insulin producing 2 cells of the pancreas. The incidence of Type 2 diabetes mellitus is increasing dramatically in our society. The research proposed in this application will improve our understanding of the pathogenesis of Type 2 diabetes and inform the development of new treatment strategies for this disease that focus on the preservation of 2 cell function.

描述（由申请人提供）：

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy.

早期糖尿病性视网膜病中脂肪基质细胞的再生治疗潜力。

DOI：
10.1371/journal.pone.0084671
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Rajashekhar G;Ramadan A;Abburi C;Callaghan B;Traktuev DO;Evans-Molina C;Maturi R;Harris A;Kern TS;March KL
通讯作者：
March KL

High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor γ signaling.