Transcriptional Regulation of Pancreas Development and Function

糖尿病是一种代谢紊乱，目前影响全球超过1.8亿人。共同 与所有形式的糖尿病相关的是内分泌胰腺中产生胰岛素的功能性β细胞的逐渐丧失。 已经证明转录因子的等级控制着细胞的发育和功能， 内分泌胰腺Islet-1（lsl-1）是一种含有同源结构域的转录因子， 胚胎前肠和成年胰岛细胞。此外，已在2型中鉴定出lsl-1突变， 提示LSL-1也可能在糖尿病的病因学中起主要作用。虽然以前的研究 使用isl-1敲除小鼠揭示了lsl-1在内分泌细胞分化的第一波中的重要作用， 在第二波内分泌细胞发育中的作用，在调节p细胞功能和生长中的作用，以及 由于LSL-1缺陷小鼠的早期胚胎致死性，尚未解决成年P-细胞扩增。 我们已经开始评估lsl-1在内分泌细胞发育的第二波，p细胞代谢中的功能 以及使用Cre/LoxP重组系统通过条件基因靶向进行p细胞扩增。在 本申请所需的初步工作，我们已经产生并测试了所有LoxP和Cre小鼠 这是所提议的实验所必需的。这项建议的具体目标是：首先，我们将确定 内分泌细胞发育第二波中lsl-1的作用，通过使用Isl-1的内胚层特异性消融， 1条鼠标线。其次，我们将研究lsl-1对p-细胞存活和葡萄糖刺激的细胞凋亡的贡献。 使用LSL-1小鼠系的β-细胞特异性缺失的胰岛素分泌。第三，我们将研究lsl-1的作用 在成年P细胞扩增期间，妊娠、高脂饮食喂养和 使用诱导型Cre重组酶系统的部分胰腺切除术。 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、β-细胞代谢、β-细胞扩增与糖尿病的发病机制。 从lsl-1的作用中获得的见解将用于设计创新的基于生物学的治疗方法， 目的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.