Decipher the Function of C2cd4a in Metabolism

项目摘要 2型糖尿病（T2 D）是由外周组织和胰腺β细胞的胰岛素抵抗引起的。 功能障碍胰岛素抵抗先于β细胞衰竭，而β细胞无法跟上胰岛素抵抗的步伐。 对胰岛素产生和分泌的需求增加导致葡萄糖耐受不良和高血糖症。的 人C2 CD 4 B-C2 CD 4A-VPS 13 C基因座具有胰腺β细胞超级增强子，并且被严重地 由迄今为止研究的几乎每个种族的T2 D风险相关GWAS SNP修饰。有 在PubMed中只有约20篇关于“C2cd 4a”的出版物，其中大多数是与此相关的关联研究。 与人类糖尿病易感性的关系。通过多组学方法，然后进行功能分析， 在小鼠中，我们发现β细胞特异性C2cd 4a消融损害胰岛素分泌。在这一建议中，通过 c2cd 4a为运动性低血糖与2型糖尿病治疗的联系提供了依据。我们将 研究C2cd 4a调控的β细胞功能，并建立以C2cd 4a为中心的通路。两个目标是 设想：在目标1中，我们将使用人类和小鼠的截短版本来定位阻遏物结构域。 C2CD 4a的表达，探讨β细胞特异性C2CD 4a在运动性低血糖发生中的作用机制 敲除小鼠在目标2中，我们将巩固C2cd 4a在细胞核中作为转录辅因子的作用， 关键β细胞基因的启动子和增强子。我们将研究C2cd 4a的调节， 基因间长非编码RNA。这些目标将促进我们对C2cd 4a作为人类糖尿病的理解 易感基因，并提供了一个蓝图，利用人类遗传学数据的生物学见解， 最终造福患者。

Project Summary Type 2 diabetes (T2D) is caused by insulin resistance in peripheral tissues and pancreatic beta-cell dysfunction. Insulin resistance precedes beta-cell failure, and the beta-cell’s inability to keep up with the increased demand of insulin production and secretion leads to glucose intolerance and hyperglycemia. The human C2CD4B-C2CD4A-VPS13C locus harbors a pancreatic beta-cell super-enhancer, and is heavily decorated by T2D risk-associated GWAS SNPs from virtually every ethnic group studied to date. There are only ~20 publications on “C2cd4a” in PubMed, the majority of which are association studies linking this locus to human diabetes susceptibility. Through a multi-omics approach followed by functional analysis in mice, we found that beta cell-specific C2cd4a ablation impairs insulin secretion. In this proposal, through C2cd4a we provide a basis to link exercise-induced hypoglycemia and type 2 diabetes treatment. We will investigate C2cd4a-regulated beta cell function, and build a pathway centered on C2cd4a. Two Aims are envisioned: in Aim 1, we will map the repressor domain using truncated versions of human and mouse C2CD4A, and investigate the mechanism of exercise-induced hypoglycemia in beta cell-specific C2cd4a knockout mice. In Aim 2, we will solidify C2cd4a’s role in the nucleus as a transcription cofactor, acting on promoters and enhancers of key beta cell genes. We will examine the regulation of C2cd4a by a novel intergenic long noncoding RNA. These Aims will advance our understanding of C2cd4a as a human diabetes susceptibility gene, and provide a blueprint to leverage human genetics data into biological insight that will eventually benefit patients.