IRS-2 FUNCTION IN BETA CELL PHYSIOLOGY

描述：（改编自申请人摘要）本修订提案 从一个建立良好的调查谁作出了开创性的贡献， 胰岛素作用领域，现在是β细胞生理学领域。这 建议基于主要研究者使用以下方法生成的最新数据 IRS 1和IRS 2小鼠的基因消融，与缺乏IRS 1和IRS 2小鼠的组合 IGF-1受体的等位基因。这些数据最近发表在《自然》杂志上， 遗传学强烈表明，IRS 2是胰腺β-淀粉样蛋白的关键决定因素， 细胞发育和β细胞中的IGF-1信号传导主要是通过 IRS 2。这些数据进一步暗示IGF-1通过IRS 2信号传导作为主要的免疫调节因子。 这是β细胞发育所需的最佳补充途径。 本应用程序将扩展这些发现，以确定潜在的机制 这些假设的关系。首先，检查组织切片， 将进行胚胎和成年小鼠胰腺的检查，以检验以下假设： IRS 2对胰岛前体细胞的增殖和存活至关重要， 确定缺乏IRS 2蛋白的小鼠发育失败的主要部位。 第二，PI 3-激酶在介导IRS 2在细胞内的某些作用中的作用。 将检查β细胞发育。第三，将进行实验， 确定它是否实际上是β细胞中特异性缺乏的IRS 2 在IRS 2基因敲除小鼠中引起糖尿病。IRS 2将被重新引入 这些动物，特别是β细胞，及其对糖尿病的影响， 监测综合症。最后，特异性地破坏IRS 2蛋白表达 将在β细胞中进行，以确定这是否足以 导致糖尿病，并且IRS 2的特异性肝破坏将作为一种 假定阴性对照。

DESCRIPTION: (Adapted from the applicant's abstract) This revised proposal is from a well established investigator who has made seminal contributions to the field of insulin action and now to the field of beta cell physiology. This proposal is based on recent data generated by the principal investigator using gene ablation in mice of IRS1 and IRS2, in combination with mice lacking one allele of the IGF-1 receptor. These data, recently published in Nature Genetics, strongly suggest that IRS2 is a key determinant of pancreatic beta cell development and that IGF-1 signaling in beta cells is largely through IRS2. The data further implicate IGF-1 signaling through IRS2 as a primary pathway that is required for an optimal complement of beta cells to develop. This application will extend these findings to determine underlying mechanisms for these hypothetical relationships. First, examination of tissue sections of embryo and adult mouse pancreas will be conducted to test the hypothesis that IRS2 is critical for proliferation and survival of islet precursor cells and identify the major site of developmental failure in mice lacking IRS2 protein. Second, the role of PI 3-kinase in mediating some of the effects of IRS2 in beta cell development will be examined. Third, experiments will be conducted to determine whether it is in fact the IRS2 lacking specifically in beta cells that causes diabetes in IRS2 gene knockout mice. IRS2 will be reintroduced into these animals, specifically in beta cells, and its effect on the diabetes syndrome monitored. Finally, disruption of IRS2 protein expression specifically in beta cells will be conducted to determine whether this is sufficient to cause diabetes, and specific hepatic disruption of IRS2 will be achieved as a presumed negative control.