Transcriptional control of pancreatic development

描述(申请人提供)：糖尿病是一种终生慢性疾病，2007年全球估计有1.8亿患者。转录因子在糖尿病病因学中的重要性的例证是，在已知的六种单基因糖尿病(MODY)中，有五种是由编码这些因子的基因突变引起的。最近的全基因组关联研究已经确定了与2型糖尿病相关的多个基因座或基因组区域；然而，这些新的基因变异和疾病关联背后的机制尚未确定。这对于10号染色体上的一个区域特别重要，因为在这种情况下，三个基因在同一个单倍型区块中，因此一起遗传：HHEX(造血表达的同源框)、KIF11(激动素相互作用因子11)和IDE(胰岛素降解酶)。因此，我们将利用遗传学和基因组学方法研究小鼠HHEX基因在内分泌胰腺分化和2-细胞功能中的作用。此外，我们将通过有条件的基因消融CREB来扩展我们在转录调控胰腺发育和功能方面的工作，现有的数据对此存在争议。我们的具体目标是：在特定目标1中，我们将利用条件性基因消融和全基因组定位分析来确定HHEX对胰腺发育和分化的贡献。在目标2中，我们将通过多种生理、生化和分子方法来描述HHEX在成熟的2-细胞的功能和增殖中的作用。在目标3中，我们将研究cAMP反应转录因子CREB如何通过细胞类型和诱导性基因缺失来控制刺激-分泌偶联和2-细胞对胰岛素的反应。公共卫生相关性：糖尿病是一个重大的健康问题，影响着美国2000多万人。产生胰岛素的β细胞不能跟上身体对胰岛素的需求是导致糖尿病的主要原因。调控β细胞增殖和功能的分子机制还远未完全了解。因此，我们将开发和开发新的遗传工具来阐明有关转录调节基因或主控基因在β细胞增殖和表现中的功能的基本问题。

DESCRIPTION (provided by applicant): Diabetes mellitus is a lifelong chronic disease with worldwide prevalence estimated at 180 million patients in 2007. The importance of transcription factors in the etiology of diabetes is exemplified by the fact that five of the six known forms of monogenic diabetes (MODY) result from mutations in genes encoding these factors. Recent genome-wide associations studies have identified multiple loci, or genomic regions, that are associated with type 2 diabetes; however, the mechanisms behind the associations of these new gene variants and disease have yet to be determined. This is of particular importance for a region on chromosome 10, because in this case three genes are in the same haplotype block and thus inherited together: HHEX (Hematopoietically expressed homeobox), KIF11 (kinesin-interacting factor 11) and IDE (insulin-degrading enzyme). Therefore, we will investigate the contribution of the mouse Hhex gene to endocrine pancreas differentiation and 2-cell function using genetic and genomic means. In addition, we will extend our work on transcriptional regulation of pancreatic development and function through conditional gene ablation of CREB, for which existing data are controversial. Our specific aims are: In specific Aim 1, we will determine the contribution of Hhex to pancreas development and differentiation using conditional gene ablation and genome- wide location analysis. In Aim 2, we will delineate the role of Hhex in function and proliferation of the mature 2-cell using multiple physiological, biochemical and molecular approaches. In Aim 3, we will investigate how the cAMP- responsive transcription factor CREB controls stimulus-secretion coupling and the 2-cells response to incretins using cell-type and inducible gene deletion. PUBLIC HEALTH RELEVANCE: Diabetes is a significant health problem, affecting more than 20 million people in the United States. Failure of the insulin-producing beta-cell to keep up with the body's need for insulin is a major contributor to diabates. The molecular mechanisms that regulate beta-cell proliferation and function are far from being understood completely. Therefore, we will develop and exploit new genetic tools to elucidate fundamental questions regarding the function of transcriptional regulators, or master genes, in proliferation and performance of beta-cells.