MECHANISMS OF BETA CELL FAILURE

描述（由申请人提供）：糖尿病是由于胰腺β细胞无法通过分泌足够的胰岛素来维持血糖。在2型糖尿病中，β细胞衰竭是胰岛素抵抗的结果，这是主要的易感代谢异常。胰岛素抵抗促进β细胞衰竭的机制尚不清楚。我们试图验证胰岛素/IGF信号通过促进胰腺导管相关细胞亚群的终末分化的旁分泌机制调节β细胞补偿以响应外周胰岛素抵抗的假设。我们进一步提出，当胰腺导管相关细胞亚群因响应胰岛素信号而加速分化而耗竭时，就会发生β细胞衰竭。我们提供的数据表明，胰岛素/ igf敏感的导管相关细胞代表了一个内分泌祖细胞群体，其特征是叉头转录因子fox01的表达。研究者的实验室已经确定Foxo1是a细胞和导管相关细胞中酪氨酸激酶信号传导的关键效应因子。通过对Foxo1进行靶向切除的小鼠，该实验室已经证明Foxo1功能缺失突变增加了β细胞的生长，并在遗传上易患β细胞衰竭的小鼠中预防糖尿病，而Foxo1功能获得与受损的β细胞增殖有关。本课题拟研究β细胞末梢分化和增殖的调控机制，并试图鉴定Foxo1阳性的胰管细胞亚群，以及Foxo1的分子靶点。在第一个目标中，我们将验证胰岛素/IGF以旁分泌方式作为信号传导刺激表达转录因子Foxo1的导管相关细胞亚群的终末分化的假设。在第二个目标中，我们将生成并表征胰腺中Foxo1功能缺失突变的小鼠，并使用RNA谱分析研究确定该转录因子的分子靶点。在第三个目标中，我们将使用遗传选择方法分离fox01阳性胰腺导管相关细胞，并检查它们的谱系以及它们的分化潜力。这些研究的结果是，在内分泌前体细胞中操纵fox01功能可能成为治疗糖尿病的辅助疗法。

DESCRIPTION (provided by applicant): Diabetes results from pancreatic beta-cells' inability to maintain euglycemia through adequate insulin secretion. In type 2 diabetes, beta-cell failure occurs as a consequence of insulin resistance, the main predisposing metabolic abnormality. The mechanism by which insulin resistance promotes beta-cell failure is unknown. We seek to test the hypothesis that insulin/IGF signaling regulates beta-cell compensation in response to peripheral insulin resistance by a paracrine mechanism promoting terminal differentiation of a subset of pancreatic duct-associated cells. We further propose that beta-cell failure occurs when this sub-population of pancreatic duct-associated cells becomes depleted as a result of accelerated differentiation in response to insulin signaling. We present data suggesting that insulin/IGF-sensitive duct-associated cells represent a population of endocrine progenitor cells, characterized by the expression of the forkhead transcription factor Foxo1. The investigator's laboratory has identified Foxo1 as a key effector of tyrosine kinase signaling in a-cells and duct-associated cells. Using mice with targeted Foxo1 ablations, this laboratory has shown that loss-of-function Foxo1 mutations increase beta-cell growth and prevent diabetes in mice genetically predisposed to beta-cell failure, while Foxo1 gain-of-function is associated with impaired beta-cell proliferation. The studies proposed in this application investigate mechanisms that regulate beta-cell terminal differentiation and proliferation and try to identify the Foxo1-positive pancreatic duct cell sub-population, as well as molecular targets of Foxo1. In the first aim, we will test the hypothesis that Insulin/IGF acts in a signaling in a paracrine fashion to stimulate terminal differentiation of a subset of duct-associated cells that express the transcription factor Foxo1. In the second aim, we will generate and characterize mice with loss-of-function Foxo1 mutations in pancreas, and identify molecular targets of this transcription factor using RNA profiling studies. In the third aim, we will use a genetic selection approach to isolate Foxo1-positive pancreatic duct-associated cells and examine their lineage as well as their differentiation potential. The upshot of these investigations is that manipulation of Foxo1 function in endocrine precursor cells may become an adjuvant therapy in the treatment of diabetes.