Regulation and Function of the Type 2 Diabetes-Associated C2CD4A/B Locus

2 型糖尿病相关 C2CD4A/B 基因座的调节和功能

基本信息

批准号：
10531864
负责人：
Michael Lee Stitzel
金额：
$ 41.63万
依托单位：
JACKSON LABORATORY
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：
2019-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531864
关键词：
Adult American Beta Cell Biochemical Biological CRISPR/Cas technology Cell model Cell physiology Cells Characteristics Chromatin Chronic Clustered Regularly Interspaced Short Palindromic Repeats Compensation Complex Coupling Data Diabetes Mellitus Diabetic mouse Disease Electron Microscopy Enhancers Environmental Risk Factor Failure Functional disorder Future Gene Deletion Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic study Glucose Goals Health system Human Immunofluorescence Immunologic Immunofluorescence Microscopy Impairment Inflammation Inflammatory Insulin Insulin Resistance Islets of Langerhans Knock-out Knowledge Life Style Link MAPK8 gene Mechanics Medical Molecular Morphology Mus NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Nutritional Palmitates Pathogenesis Phase Phenotype Physiological Population Predisposition Prevention Public Health Publishing Regulation Regulatory Element Research Design Rodent Role Site Stimulus Stress Stretching Testing Therapeutic Variant blood glucose regulation cell type cytokine diabetes pathogenesis diabetogenic empowerment functional genomics genetic variant genome editing genome wide association study in vivo insight insulin secretion islet mouse model novel novel therapeutics nuclear factors of activated T-cells overexpression prevent response risk variant stressor success transcription factor transcriptomics

项目摘要

PROJECT SUMMARY Diabetes afflicts approximately 29 million adult Americans (9.3% of the total population), 90-95% of whom have type 2 diabetes (T2D). T2D is a complex disease with both genetic and environmental components and ultimately manifests when pancreatic islets fail to secrete sufficient insulin to compensate for increased insulin resistance. Despite the success of genome-wide association studies (GWAS) in linking >100 loci to islet dysfunction and T2D, we still lack the mechanistic insights necessary to develop novel treatments and preventions. Detailed molecular and phenotypic analyses of each T2D-associated GWAS locus are thus essential to determine how they contribute to islet dysfunction and diabetes. We have recently linked altered C2CD4A/B expression to genetic risk of islet dysfunction and T2D. Our overall objective is to understand the islet/beta cell regulation and function of the C2CD4A/B locus in physiologic and diabetogenic states. We hypothesize that these genes regulate stimulus-secretion coupling and that chronic activation of C2CD4A/B by genetic and/or environmental risk factors contributes to the declines in first-phase insulin secretion that are hallmarks of the early stages of T2D. To test this hypothesis, we will determine the regulatory circuitry controlling C2CD4A/B responses to inflammatory stressors and determine the effect of T2D-associated GWAS variants on C2CD4A/B activity (Aim 1). In parallel, we will dissect the beta cell functions of C2CD4A and C2CD4B in glucose-stimulated insulin secretion (Aim 2). Finally, we will assess the in vivo effects of deleting these genes in a polygenic T2D mouse model (Aim 3). Together, these aims will provide fundamental, mechanistic insights into the regulation and function of the C2CD4A/B locus and will delineate the roles of these genes in islet function and T2D pathogenesis. More broadly, we anticipate the study of this locus will provide new perspectives/insights into the mechanics of insulin secretion and beta cell compensation. The cellular and mouse models that we will create to dissect the regulation and function of the C2CD4A/B locus in diabetes pathogenesis will empower future analyses of novel therapeutic molecules and approaches to target this locus to prevent and treat diabetes.

项目摘要糖尿病遭受了约2900万成年美国人（占总人口的9.3％），其中90-95％ 2型糖尿病（T2D）。 T2D是一种复杂的疾病，具有遗传和环境成分，当胰岛无法分泌足够的胰岛素以补偿增加的胰岛素时，最终表现出来反抗。尽管全基因组关联研究（GWAS）在连接> 100个基因座与胰岛方面取得了成功功能障碍和T2D，我们仍然缺乏开发新疗法和预防。因此，每个T2D相关的GWAS基因座的详细分子和表型分析是确定它们如何对胰岛功能障碍和糖尿病的贡献至关重要。我们最近链接了 C2CD4A/B表达胰岛功能障碍和T2D的遗传风险。我们的总体目标是了解 C2CD4A/B基因座的胰岛/β细胞调节以及生理和糖尿病态中的功能。我们假设这些基因调节刺激 - 分泌耦合以及C2CD4A/B的慢性激活遗传和/或环境风险因素导致第一阶段胰岛素分泌的下降是 T2D早期阶段的标志。为了检验这一假设，我们将确定调节电路控制C2CD4A/B对炎症应激源的反应，并确定与T2D相关的GWA的作用 C2CD4A/B活动的变体（AIM 1）。同时，我们将剖析C2CD4A和葡萄糖刺激的胰岛素分泌中的C2CD4B（AIM 2）。最后，我们将评估删除的体内影响这些基因在多基因T2D小鼠模型中（AIM 3）。这些目标共同提供基本的，对C2CD4A/B基因座的调节和功能的机理见解，并将描述这些基因在胰岛功能和T2D发病机理中。更广泛地，我们预计该基因座的研究将会提供有关胰岛素分泌和β细胞补偿机制的新观点/见解。这我们将创建的蜂窝和小鼠模型，以剖析C2CD4A/B基因座的调节和功能糖尿病的发病机理将赋予对新的治疗分子的未来分析，并促进靶向方法这个基因座预防和治疗糖尿病。