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为特征。胰腺细胞通过调节胰岛素分泌来动态响应血糖的波动。增加对这些动态胰岛素生成细胞功能的分子信号机制的理解将有助于开发更有效的治疗方法。TCPTP是一种普遍表达的非受体酪氨酸蛋白磷酸酶。全身TCPTP缺失的小鼠表现出造血缺陷并在出生后死亡，从而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确定，但越来越多的证据表明它在细胞功能中起作用。全基因组关联筛选确定PTPN2是参与1型糖尿病发病机制的易感基因。此外，TCPTP还能调控细胞因子诱导的细胞凋亡。此外，TCPTP调节内质网应激信号在葡萄糖反应的MIN6 -细胞。此外，TCPTP是胰岛素、瘦素和c-Src信号通路的关键调节因子，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。我们将产生胰腺TCPTP敲除（KO）小鼠来研究TCPTP在胰腺中丢失的直接后果。此外，我们将确定TCPTP敲除和药理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：(1)胰腺TCPTP KO小鼠表现出糖耐量受损和葡萄糖刺激胰岛素分泌（GSIS）减弱。（ii） GSIS的分泌缺陷在离体研究中得到证实，表明其作用是细胞自主的。（iii） MIN6 -细胞中TCPTP的敲除和药理抑制可减弱GSIS。（iv）在细胞中鉴定出STAT3为TCPTP底物。本研究的目标是研究TCPTP在胰腺内分泌功能中的生理作用，并为糖尿病的治疗提供长期的治疗方法。

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.