Role of T cell protein-tyrosine phosphatase in pancreatic islet function

描述(申请人提供)：2型糖尿病是最常见的代谢性疾病之一，以高胰岛素血症、胰岛素抵抗和胰岛分泌功能缺陷(S)为特征。胰腺�细胞通过调节胰岛素的分泌，动态地对血糖的波动做出反应。对这些动态的、产生胰岛素的细胞功能的分子信号机制的进一步了解将有助于开发更有效的治疗方法。TCPTP是一种广泛表达的非受体蛋白--酪氨酸磷酸酶。全身TCPTP缺失的小鼠表现出造血缺陷并在出生后死亡，因此阻碍了对其代谢表型的详细评估。TCPTP在胰腺中的功能在很大程度上仍未得到解决，但越来越多的证据表明，TCPTP在�细胞功能中发挥了作用。全基因组关联筛查发现PTPN2是参与1型糖尿病发病机制的易感基因。此外，TCPTP还调节细胞因子诱导的�-细胞的凋亡。此外，TCPTP在葡萄糖反应的MIN6�细胞中调节内质网应激信号。此外，TCPTP是胰岛素、瘦素和c-Src信号通路的关键调节者，这些信号通路在�细胞功能中发挥重要作用。为了确定TCPTP在胰岛中的生理作用，我们将采用两种互补的方法。我们将建立胰腺TCPTP基因敲除(KO)小鼠，以研究体内TCPTP缺失在胰腺中的直接后果。此外，我们还将确定TCPTP基因敲除和药物抑制对�细胞功能的影响。同样重要的是对介导TCPTP作用的分子机制的剖析。在初步研究中，我们证明：(I)胰腺TCPTP KO小鼠表现出糖耐量受损和葡萄糖刺激的胰岛素分泌(GSIS)减弱。(Ii)GSIS的分泌缺陷在体外研究中得到证实，表明这种影响是细胞自主的。(3)TCPTP基因敲除和对MIN6�-细胞的药理抑制可减弱GSI。(4)确定STAT3为�-细胞中的TCPTP底物。这项建议的主要目标是研究TCPTP在胰腺内分泌功能中的生理作用，并以产生治疗糖尿病的长期目标为目标。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus is one of the most prevalent metabolic diseases that is characterized by hyperinsulinemia, insulin resistance, and defect(s) in islet secretory function. Pancreatic �-cells dynamically respond to fluctuations in blood glucose with the regulated secretion of insulin. Increased understanding of the molecular signaling mechanisms that underlie the function of these dynamic, insulin-producing cells will aid in the development of more effective therapies. TCPTP is a ubiquitously expressed non-receptor protein-tyrosine phosphatase. Mice with whole-body TCPTP deletion exhibit hematopoietic defects and die after birth thus hampering detailed assessment of their metabolic phenotype. The function of TCPTP in the pancreas remains largely unresolved, but a growing body of evidence suggests a role in �-cell function. Genome-wide association screens identified PTPN2 as a susceptibility gene involved in the pathogenesis of type 1 diabetes. In addition, TCPTP regulates cytokine-induced �-cell apoptosis. Moreover, TCPTP modulates endoplasmic reticulum stress signaling in the glucose-responsive MIN6 �-cells. Further, TCPTP is a key regulator of insulin, leptin, and c-Src signaling pathways which play important roles in �-cell function. To determine the physiological role of TCPTP in pancreatic islets, we will employ two complementary approaches. We will generate pancreas TCPTP knockout (KO) mice to study the direct consequences of TCPTP loss in the pancreas in vivo. In addition, we will determine the effects of TCPTP knockdown and pharmacological inhibition on �-cell function. Equally important is the dissection of the molecular mechanisms mediating TCPTP actions. In preliminary studies we demonstrated that: (i) pancreas TCPTP KO mice exhibited impaired glucose tolerance and attenuated glucose-stimulated insulin secretion (GSIS). (ii) The secretory defect in GSIS was confirmed in ex vivo studies indicating that the effects were cell autonomous. (iii) TCPTP knockdown and pharmacological inhibition in MIN6 �-cells attenuated GSIS. (iv) Identified STAT3 as a TCPTP substrate in �-cells. The broad goals of this proposal are to investigate the physiological role of TCPTP in pancreas endocrine function with the long-term aim of generating therapies for the treatment of diabetes.