Decipher the Function of C2cd4a in Metabolism

解读 C2cd4a 在代谢中的功能

基本信息

批准号：
10594862
负责人：
Taiyi Diana Kuo
金额：
$ 39.93万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594862
关键词：
Ablation Affect Agonist Aldolase B Amino Acid Sequence Beta Cell Binding Biological Biological Assay Cell Maturation Cell Nucleus Cell physiology Cells ChIP-seq Chromatin Closure by clamp Co-Immunoprecipitations Consensus Coupled DNA Binding Domain Data Diabetes Mellitus Disease Enhancers Ethnic Population Exercise Exons FOXO1A gene Failure Female Foundations Frequencies Functional disorder GLP-I receptor Gene Expression Regulation Genes Genetic Transcription Glucose Glucose Intolerance Glyburide High Fat Diet Human Human Genetics Hyperglycemia Hypoglycemia Impairment Insulin Insulin Resistance Intercistronic Region Knock-out Knockout Mice Lactate Transporter Link Maps Messenger RNA Metabolism Modeling Molecular Mus Mutation Non-Insulin-Dependent Diabetes Mellitus OGTT Pathogenesis Pathway interactions Patients Peripheral Phenotype Plasma Predisposition Production Proteins PubMed Publications Pyruvate Regulation Reporter Reporting Repression Role Secondary to Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Site Strenuous Exercise Structure of beta Cell of islet Sulfonylurea Compounds Susceptibility Gene Testing Therapeutic Tissues Untranslated RNA Work cell dedifferentiation chromosome conformation capture cofactor db/db mouse derepression diabetes mellitus therapy diabetes risk exenatide experience experimental study gain of function genome wide association study genome-wide genome-wide analysis in vivo insight insulin secretion islet lactate dehydrogenase A male mouse model multiple omics novel precision medicine prevent promoter protein complex response transcription factor virtual

项目摘要

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.

项目概要 2 型糖尿病 (T2D) 是由外周组织和胰腺 β 细胞的胰岛素抵抗引起的胰岛素抵抗先于β细胞衰竭，而β细胞无法跟上。胰岛素产生和分泌的需求增加导致葡萄糖不耐受和高血糖。人类 C2CD4B-C2CD4A-VPS13C 基因座含有胰腺 β 细胞超级增强子，并且迄今为止研究的几乎每个种族群体中都有与 T2D 风险相关的 GWAS SNP 进行装饰。 PubMed 上只有约 20 篇关于“C2cd4a”的出版物，其中大多数是关联此的关联研究通过多组学方法，然后进行功能分析，确定人类糖尿病易感性的基因座。在小鼠中，我们发现β细胞特异性C2cd4a消融会损害胰岛素分泌。 C2cd4a 我们提供了将运动引起的低血糖与 2 型糖尿病治疗联系起来的基础。研究 C2cd4a 调节的 β 细胞功能，并建立以 C2cd4a 为中心的通路，其两个目标是。设想：在目标 1 中，我们将使用人类和小鼠的截短版本来绘制阻遏物结构域 C2CD4A，并研究β细胞特异性C2CD4a运动诱发低血糖的机制在目标 2 中，我们将巩固 C2cd4a 在细胞核中作为转录辅助因子的作用，作用于我们将通过一种新的方法来检查 C2cd4a 的调控。这些目标将增进我们对 C2cd4a 作为人类糖尿病的理解。易感性基因，并提供利用人类遗传学数据进行生物学洞察的蓝图，这将最终造福患者。