The JAZF1 Gene and Type 2 Diabetes

JAZF1 基因和 2 型糖尿病

• 批准号: 7767344
• 负责人: Jeffrey Sklar
• 金额: $ 35.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767344
• 关键词: Affect; Alleles; Antibodies; Area; Binding; Biochemical Pathway; Cell Nucleus; Cells; Co-Immunoprecipitations; Complementary DNA; Constitutional; Cultured Cells; Cytoplasm; Development; Disease; Endometrial Stromal Cell; Endometrial Stromal Tumors; Exons; Fibroblasts; Gene Fusion; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Screening; Genome; Glucose; Glucose tolerance test; Haplotypes; Height; Human; Human Genome; Hyperglycemia; Hypoglycemia; IGF1 gene; Immunohistochemistry; Individual; Inherited; Insulin; Introns; Investigation; Knockout Mice; Laboratories; Light; Link; Linkage Disequilibrium; Lymphocyte; Malignant neoplasm of prostate; Messenger RNA; Microarray Analysis; Mus; Non-Insulin-Dependent Diabetes Mellitus; Northern Blotting; Nuclear Orphan Receptor; Patients; Predisposition; Prevalence; Procedures; Production; Proteins; RNA; RNA analysis; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Serum; Single Nucleotide Polymorphism; Structure of beta Cell of islet; Surveys; Tissues; Tonsil; Trans-Splicing; Transgenes; Variant; Western Blotting; Wild Type Mouse; Yeasts; base; cell type; disorder risk; gene function; genome wide association study; glucose metabolism; human tissue; in vivo; insulin secretion; insulin sensitivity; mRNA Precursor; public health relevance; research study; response; tissue/cell culture; trait; yeast two hybrid system

DESCRIPTION (provided by applicant): Studies involving surveys of single nucleotide polymorphisms (SNPs) throughout the entire human genome have recently detected an association of a SNP in the first exon of the JAZF1 gene and individuals with type 2 diabetes. The biologic basis of this association is unknown. Moreover, little is known about the function of this gene in general. Its protein product is present in most human cells and is located in both the cytoplasm and the nucleus. The 5' end of JAZF1 is part of a gene fusion present in endometrial stromal tumors, and pre-mRNA transcribed from the gene participates in trans-splicing with pre-mRNA of a second gene within normal endometrial stromal cells. One report has found that JAZF1 protein co-precipitates with an orphan nuclear receptor, NR2C2. Whole genome association studies similar to those involving type 2 diabetes have found that a JAZF1 SNP physically linked closely to that correlated with type 2 diabetes is commonly found in people of increased height and a separate SNP in intron 2, outside the area of linkage disequilibrium with the intron 1 SNPs, is associated with decreased risk of prostate cancer. In preliminary studies, we have shown that the SNP associated with type 2 diabetes leads to increased pre-mRNA from the JAZF1 gene in fibroblasts and tonsil tissue. Seemingly consistent with that finding, our studies have also shown that knockout mice lacking functional JAZF1 have low basal serum insulin levels and a hypoglycemic response to glucose challenge. In research proposed in this application, we will further characterize in lymphocytes and various human tissues the altered expression of JAZF1 alleles containing the SNP associated with type 2 diabetes. We will conduct hyperinsulinemic-euglycemic and hyperglycemic clamp experiments on the JAZF-/- mice to determine if the effect already detected on insulin and glucose metabolism is related to changes in insulin sensitivity and/or insulin secretion from pancreatic beta cells, compared to wild type mice. We will also determine whether expression of JAZF1 transgenes inserted into cultured cells alters insulin sensitivity and/or insulin secretion. Finally, we will identify proteins to which JAZF1 binds and changes in levels of RNA induced by JAZF1. Taken together, these studies will greatly advance understanding of how JAZF1 in particular and SNP variants in general may influence susceptibility to type 2 diabetes and other diseases. PUBLIC HEALTH RELEVANCE: The research proposed in this application is relevant to whole genome association (WGA) studies of inherited risk of diseases and constitutional traits; mechanisms by which single nucleotide polymorphisms (SNP) are associated with altered risk of disease; polygenic risks of disease; genetic susceptibility to type 2 diabetes; and the function of the JAZF1 gene in normal and dysfunctional cells.

描述（由申请人提供）：涉及整个人类基因组的单核苷酸多态性（SNP）调查的研究最近发现JAZF1基因第一外显子的SNP与2型糖尿病个体有关。这种关联的生物学基础尚不清楚。此外，人们对该基因的一般功能知之甚少。它的蛋白产物存在于大多数人类细胞中，位于细胞质和细胞核中。JAZF1的5'端是子宫内膜间质肿瘤中存在的基因融合的一部分，从该基因转录的前mrna参与了正常子宫内膜间质细胞中第二个基因的前mrna的反式剪接。一份报告发现JAZF1蛋白与孤儿核受体NR2C2共沉淀。类似于涉及2型糖尿病的全基因组关联研究发现，与2型糖尿病密切相关的JAZF1 SNP通常在身高增加的人群中发现，在与内含子1 SNP连锁不平衡区域之外的内含子2中有一个单独的SNP与前列腺癌风险降低有关。在初步研究中，我们发现与2型糖尿病相关的SNP导致成纤维细胞和扁桃体组织中JAZF1基因的前mrna增加。似乎与这一发现一致，我们的研究还表明，缺乏功能性JAZF1的敲除小鼠具有较低的基础血清胰岛素水平和对葡萄糖挑战的低血糖反应。在本申请提出的研究中，我们将进一步表征淋巴细胞和各种人体组织中含有与2型糖尿病相关的SNP的JAZF1等位基因的表达改变。我们将对JAZF-/-小鼠进行高胰岛素-正糖和高血糖钳夹实验，以确定与野生型小鼠相比，已经检测到的对胰岛素和葡萄糖代谢的影响是否与胰岛素敏感性和/或胰腺β细胞胰岛素分泌的变化有关。我们还将确定插入培养细胞的JAZF1转基因的表达是否会改变胰岛素敏感性和/或胰岛素分泌。最后，我们将鉴定JAZF1结合的蛋白以及JAZF1诱导的RNA水平的变化。综上所述，这些研究将极大地促进对JAZF1和SNP变异如何影响2型糖尿病和其他疾病易感性的理解。