Decipher the Function of C2cd4a in Metabolism

项目摘要 2型糖尿病(T2D)是由外周组织和胰岛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 对胰岛素产生和分泌的需求增加会导致葡萄糖耐量增加和高血糖。这个 人类C2CD4B-C2CD4A-VPS13C基因座含有胰腺β细胞超级增强子，并严重 由T2D风险相关的GWAS SNPs装饰，这些SNP来自到目前为止研究的几乎每个种族群体。确实有 PubMed上只有大约20篇关于C2cd4a的文章，其中大部分是关联研究 人类糖尿病易感性的基因座。通过多组学方法，然后进行功能分析 小鼠，我们发现β细胞特异性的C2cd4a消融会损害胰岛素的分泌。在这份提案中，通过 C2cd4a为将运动诱导低血糖与2型糖尿病治疗联系起来提供依据。我们会 研究C2cd4a调节的β细胞功能，构建以C2cd4a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映射抑制物结构域 C2CD4a，并探讨运动诱导β细胞特异性C2cd4a低血糖的机制 基因敲除老鼠。在目标2中，我们将巩固C2cd4a在细胞核中作为转录辅助因子的作用，作用于 关键的β细胞基因的启动子和增强子。我们将通过一本小说来研究C2cd4a的调节 基因间的长非编码RNA。这些目标将促进我们对C2cd4a作为人类糖尿病的理解 易感基因，并提供了一张利用人类遗传学数据进行生物学洞察的蓝图 最终使患者受益。

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.