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

• 批准号: 10304883
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304883
• 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; Complex; Coupling; Data; Diabetes Mellitus; Diabetic mouse; Disease; Electron Microscopy; Enhancers; Environmental Risk Factor; Failure; Financial compensation; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; 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; Morphology; Mus; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Palmitates; Pancreas; Pathogenesis; Phase; Physiological; Population; Predisposition; Prevention; Public Health; Publishing; Regulation; Research Design; Rodent; Role; Site; Stimulus; Stress; Stretching; Testing; Therapeutic; Variant; blood glucose regulation; cell type; cytokine; diabetes pathogenesis; diabetogenic; functional genomics; genetic variant; genome editing; genome wide association study; in vivo; insight; insulin secretion; islet; molecular phenotype; mouse model; novel; novel therapeutics; overexpression; prevent; response; risk variant; stressor; success; transcription factor; transcriptomics

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 糖尿病困扰着大约2900万成年美国人（占总人口的9.3%），其中90-95%患有糖尿病。 2型糖尿病（T2 D）。T2 D是一种复杂的疾病，具有遗传和环境因素， 当胰岛不能分泌足够的胰岛素来补偿增加的胰岛素时， 阻力尽管全基因组关联研究（GWAS）成功地将>100个基因座与胰岛β细胞相关， 尽管我们对T2 D和T2功能障碍的认识不足，但我们仍然缺乏开发新疗法所需的机制见解， 预防。因此，每个T2 D相关GWAS基因座的详细分子和表型分析如下： 关键是确定它们如何导致胰岛功能障碍和糖尿病。我们最近发现 C2 CD 4 A/B表达与胰岛功能障碍和2型糖尿病的遗传风险我们的总体目标是了解 胰岛/β细胞调节和C2 CD 4 A/B基因座在生理和糖尿病状态下的功能。我们 假设这些基因调节刺激-分泌偶联和C2 CD 4 A/B慢性活化， 遗传和/或环境风险因素导致第一时相胰岛素分泌下降， T2 D早期阶段的标志。为了验证这一假设，我们将确定 控制C2 CD 4 A/B对炎症应激的反应，并确定T2 D相关GWAS的作用 变体对C2 CD 4 A/B活性的影响（目的1）。与此同时，我们将剖析C2CD 4A的β细胞功能， C2CD 4 B在葡萄糖刺激的胰岛素分泌中的作用（目的2）。最后，我们将评估在体内的影响，删除 这些基因在多基因T2 D小鼠模型中（目的3）。总之，这些目标将提供基本的， 对C2 CD 4 A/B基因座的调节和功能的机制性见解，并将描述以下作用： 这些基因在胰岛功能和T2 D发病机制中发挥作用。更广泛地说，我们预计对这一位点的研究将 为胰岛素分泌和β细胞补偿机制提供了新的视角/见解。的 细胞和小鼠模型，我们将创建解剖的调控和功能的C2 CD 4 A/B基因座， 糖尿病发病机制将使未来分析新的治疗分子和方法，以靶向 预防和治疗糖尿病。