MECHANISMS OF BETA CELL FAILURE

描述（由申请人提供）：糖尿病是由于胰腺β细胞无法通过充分的胰岛素分泌维持正常分泌所致。在2型糖尿病中，β细胞衰竭是胰岛素抵抗的结果，胰岛素抵抗是主要的诱发代谢异常。胰岛素抵抗促进β细胞衰竭的机制尚不清楚。我们试图检验胰岛素/IGF信号调节β细胞补偿的假设，以响应外周胰岛素抵抗的旁分泌机制，促进终末分化的一个子集的胰腺导管相关细胞。我们进一步提出，当胰管相关细胞的该亚群由于响应于胰岛素信号传导的加速分化而变得耗尽时，β细胞衰竭发生。我们目前的数据表明，胰岛素/IGF-敏感的导管相关细胞代表内分泌祖细胞的人口，其特征在于叉头转录因子Foxo 1的表达。研究者的实验室已经确定Foxo 1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子。使用具有靶向Foxo 1消融的小鼠，该实验室已经表明，Foxo 1功能丧失突变增加了β细胞生长，并预防了遗传上易患β细胞衰竭的小鼠的糖尿病，而Foxo 1功能获得与β细胞增殖受损有关。本申请中提出的研究调查了调节β细胞终末分化和增殖的机制，并试图鉴定Foxo 1阳性胰管细胞亚群以及Foxo 1的分子靶标。在第一个目标中，我们将检验胰岛素/IGF以旁分泌方式在信号传导中起作用以刺激表达转录因子Foxo 1的导管相关细胞亚群的终末分化的假设。在第二个目标中，我们将产生和表征胰腺功能缺失Foxo 1突变的小鼠，并使用RNA分析研究鉴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Foxo 1阳性胰腺导管相关细胞，并检查其谱系以及其分化潜力。这些研究的结果是，操纵内分泌前体细胞中的Foxo 1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.