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

项目总结 糖尿病困扰着大约2900万美国成年人(占总人口的9.3%)，其中90%-95%的人患有糖尿病 2型糖尿病(T2D)。T2D是一种复杂的疾病，包括遗传和环境因素，以及 最终表现为胰岛不能分泌足够的胰岛素来补偿增加的胰岛素 抵抗。尽管全基因组关联研究成功地将100个基因座与胰岛联系起来 功能障碍和T2D，我们仍然缺乏必要的机械洞察来开发新的治疗方法和 预防措施。因此，每个与T2D相关的GWAS座的详细的分子和表型分析 对于确定它们如何导致胰岛功能障碍和糖尿病至关重要。我们最近改变了链接 C2CD4A/B表达与胰岛功能障碍和T2D的遗传风险我们的总体目标是了解 生理和非生理性状态下C2CD4A/B位点的胰岛/β细胞调节和功能。我们 假设这些基因调节刺激-分泌偶联和C2CD4A/B通过 遗传和/或环境风险因素导致第一时相胰岛素分泌下降 T2D早期阶段的特征。为了验证这一假设，我们将确定调节电路 控制C2CD4A/B对炎性应激源的反应并确定T2D相关GWAs的作用 C2CD4A/B活性的变体(目标1)。同时，我们将剖析C2CD4A的β细胞功能和 C2CD4B在葡萄糖刺激的胰岛素分泌中(目标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(目标3)。总而言之，这些目标将提供根本的、 对C2CD4A/B基因座的调节和功能的机械性见解，并将描绘出 这些基因在胰岛功能和T2D发病机制中起重要作用。更广泛地说，我们预计对这一基因座的研究将 对胰岛素分泌和β细胞补偿的机制提供新的视角/见解。这个 我们将创建的细胞和小鼠模型来剖析C2CD4A/B基因座的调节和功能 糖尿病发病机制将使未来对新的治疗分子和靶向方法的分析成为可能 这个基因座可以预防和治疗糖尿病。

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.