Transcriptional Regulation of Pancreas Development and Function

糖尿病是一种代谢性疾病，目前全球有超过1.8亿人受到影响。普普通通 对于所有形式的糖尿病来说，内分泌胰腺中产生胰岛素的功能性胰岛细胞逐渐丧失。 已经证实转录因子的层次结构控制着细胞的发育和功能。 内分泌胰腺。胰岛-1(Ilet-1，LSL-1)是一种含有转录因子的同源结构域，表达于 胚胎前肠，以后在成体胰岛细胞中。此外，在2型中发现了LSL-1突变 糖尿病患者提示LSL-1在糖尿病的病因中也可能发挥重要作用。虽然之前的研究 利用ISL-1基因敲除小鼠揭示了LSL-1在第一波内分泌细胞分化中的重要作用，其 在第二波内分泌细胞发育中的作用，调节p细胞的功能和生长，以及 由于LSL-1缺陷小鼠的早期胚胎致死性，成年P细胞的扩增尚未得到解决。 我们已经开始评估LSL-1在内分泌细胞发育的第二波，即p细胞代谢中的作用 以及通过使用Cre/loxP重组系统的条件基因打靶来扩增p细胞。在……里面 此应用程序所需的准备工作我们已经生成并测试了所有loxP和Cre小鼠 对拟议的实验来说是必要的。这项建议的具体目的是：第一，我们将确定 通过内胚层特异性消融ISL-1，LSL-1在第二波内分泌细胞发育中的作用 1个小鼠品系。第二，我们将研究LSL-1在p细胞存活和葡萄糖刺激中的作用。 胰岛素分泌采用p细胞特异性缺失的LSL-1小鼠品系。第三，我们将研究LSL-1的作用 在成年P细胞扩增过程中，由于妊娠、高脂饮食和 使用可诱导的Cre重组酶系统的胰腺部分切除术。 总之，这些研究将进一步加深我们对控制第二个基因的转录网络的理解 内分泌细胞分化波、p细胞代谢、p细胞扩张与糖尿病的发病机制。 从LSL-1的作用中获得的见解将被用于设计基于生物的创新疗法 目标是为糖尿病提供新的治疗方法。

Diabetes mellitus is a metabolic disorder that currently affects over 180 million people worldwide. Common to all forms of diabetes is the gradual loss of functional insulin-producing p-cells in the endocrine pancreas. A hierarchy of transcription factors has been demonstrated to control the development and function of the endocrine pancreas. Islet-1 (lsl-1), is a homeo-domain containing transcription factor that is expressed in embryonic foregut and later in adult islet cells. Furthermore, lsl-1 mutations have been identified in type 2 diabetics suggesting that lsl-1 may also play a major role in the etiology of diabetes. While previous studies using isl-1 knockout mice have revealed a vital role for lsl-1 in first wave of endocrine cell differentiation, its role in the second wave of endocrine cell development, in regulation of p-cell function and growth, as well as in adult p-cell expansion have not been addressed due to the early embryonic lethality of lsl-1 deficient mice. We have begun to assess lsl-1 function in second wave of endocrine cell development, p-cell metabolism and p-cell expansion through conditional gene targeting using the Cre/LoxP recombination system. In preliminary work required for this application we have generated and tested all LoxP and Cre mice necessary for the proposed experiments. The specific aims of this proposal are: First, we will determine the role of lsl-1 during second wave of endocrine cell development by using an endoderm-specific ablation of Isl- 1 mouse line. Second, we will investigate the contribution of lsl-1 to p-cell survival and glucose stimulated insulin secretion using a p-cell-specific deletion of lsl-1 mouse line. Third, we will investigate the role of lsl-1 during adult p-cell expansion in to increased metabolic demands of pregnancy, high fat diet feeding and partial pancreatectomy using an inducible Cre-recombinase system. Together these studies will further our understanding of the transcriptional networks controlling the second wave of endocrine cell differentiation, p-cell metabolism, p-cell expansion and the pathogenesis of diabetes. Insights gained from the role of lsl-1 will be used for designing innovative biologically based therapy with the goal to provide novel treatments for diabetes.