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

T细胞蛋白酪氨酸磷酸酶在胰岛功能中的作用

基本信息

批准号：
9277450
负责人：
Fawaz George Haj
金额：
$ 34.15万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277450
关键词：
Affect Apoptosis Attenuated Beta Cell Biochemical Birth Blood Glucose Cell Line Cell Proliferation Cell physiology Cells Data Defect Development Diabetes Mellitus Dissection Enterobacteria phage P1 Cre recombinase Exhibits Experimental Designs Genetically Engineered Mouse Glucose Goals Hematopoietic High Fat Diet Hyperinsulinism Insulin Insulin Resistance Insulin Signaling Pathway Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knock-out Knockout Mice Leptin Mediating Metabolic Metabolic Diseases Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathogenesis Pharmacology Physiological Play Protein Tyrosine Phosphatase Regulation Role SRC gene STAT3 gene Signal Pathway Signal Transduction Susceptibility Gene T-cell protein tyrosine phosphatase Testing Therapeutic Intervention blood glucose regulation cytokine effective therapy endoplasmic reticulum stress genome wide association study glucose tolerance impaired glucose tolerance in vivo insulin secretion insulin sensitivity insulin signaling insulinoma islet knock-down lentiviral-mediated metabolic phenotype mouse model pancreatic islet function promoter public health relevance reconstitution

项目摘要

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.

描述（由申请人提供）：2型糖尿病是最常见的代谢性疾病之一，其特征在于高胰岛素血症、胰岛素抵抗和胰岛分泌功能缺陷。胰腺β细胞对血糖的波动作出动态反应，调节胰岛素的分泌。增加对这些动态的胰岛素产生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是一种广泛表达的非受体蛋白酪氨酸磷酸酶。具有全身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得到解决，但越来越多的证据表明它在β细胞功能中发挥作用。全基因组关联筛选将PTPN 2鉴定为参与1型糖尿病发病机制的易感基因。此外，TCPTP还能调节精氨酸诱导的β细胞凋亡。此外，TCPTP调节内质网应激信号在葡萄糖响应的MIN 6 β-细胞。此外，TCPTP是胰岛素、瘦素和c-Src信号通路的关键调节剂，这些信号通路在β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）小鼠以研究体内胰腺中TCPTP损失的直接后果。此外，我们将确定TCPTP敲低和药理学抑制对β细胞功能的影响。同样重要的是解剖介导TCPTP作用的分子机制。在初步研究中，我们证明：（i）胰腺TCPTP KO小鼠表现出受损的葡萄糖耐量和减弱的葡萄糖刺激的胰岛素分泌（GSIS）。(ii)在离体研究中证实了GSIS的分泌缺陷，表明其作用是细胞自主的。(iii)在MIN 6 β细胞中TCPTP敲低和药理学抑制减弱了GSIS。(iv)在β-细胞中鉴定STAT 3为TCPTP底物。该提案的广泛目标是研究TCPTP在胰腺内分泌功能中的生理作用，其长期目标是产生治疗糖尿病的疗法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury.

DOI：
10.1016/j.metabol.2017.07.009
发表时间：
2017-11
期刊：
Metabolism: clinical and experimental
影响因子：
0
作者：
Ito Y;Hsu MF;Bettaieb A;Koike S;Mello A;Calvo-Rubio M;Villalba JM;Haj FG
通讯作者：
Haj FG

Decreased adiposity and enhanced glucose tolerance in shikonin treated mice.

DOI：
10.1002/oby.21263
发表时间：
2015-11
期刊：
Obesity (Silver Spring, Md.)
影响因子：
0
作者：
Bettaieb A;Hosein E;Chahed S;Abdulaziz A;Kucera HR;Gaikwad NW;Haj FG
通讯作者：
Haj FG

Chow fed UC Davis strain female Lepr fatty Zucker rats exhibit mild glucose intolerance, hypertriglyceridemia, and increased urine volume, all reduced by a Brown Norway strain chromosome 1 congenic donor region.

DOI：
10.1371/journal.pone.0188175
发表时间：
2017
期刊：
PloS one
影响因子：
3.7
作者：
Warden CH;Bettaieb A;Min E;Fisler JS;Haj FG;Stern JS
通讯作者：
Stern JS

Catechin and quercetin attenuate adipose inflammation in fructose-fed rats and 3T3-L1 adipocytes.

DOI：
10.1002/mnfr.201400631
发表时间：
2015-04
期刊：
MOLECULAR NUTRITION & FOOD RESEARCH
影响因子：
5.2
作者：
Vazquez Prieto, Marcela A.;Bettaieb, Ahmed;Rodriguez Lanzi, Cecilia;Soto, Veronica C.;Perdicaro, Diahann J.;Galmarini, Claudio R.;Haj, Fawaz G.;Miatello, Roberto M.;Oteiza, Patricia I.
通讯作者：
Oteiza, Patricia I.

S-nitrosylation of endogenous protein tyrosine phosphatases in endothelial insulin signaling.