A NOVEL ROLE FOR PTPN2 IN INTESTINAL EPITHELIAL BARRIER REGULATION

PTPN2 在肠上皮屏障调节中的新作用

• 批准号: 8453364
• 负责人: Declan McCole
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-05 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453364
• 关键词: Address; Affect; American; Bacteria; Candidate Disease Gene; Celiac Disease; Cell Line; Cells; Chronic; Chronic Disease; Crohn' s disease; Cytokine Signaling; Defect; Development; Disease; Dominant-Negative Mutation; Epithelial; Epithelial Cells; Epithelium; Event; Exhibits; Functional disorder; Genes; Genetic; Genetic Markers; Hematopoietic; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Insulin-Dependent Diabetes Mellitus; Interferons; Intestines; Link; Maintenance; Mediating; Mediator of activation protein; Mus; Mutate; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Receptor Protein Tyrosine Phosphatase Gene; Outcome; Pathogenesis; Patients; Permeability; Phosphoric Monoester Hydrolases; Play; Post-Translational Protein Processing; Protein Tyrosine Phosphatase; Regulation; Rest; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Staging; Stress; Testing; Tight Junctions; Tissues; Ulcerative Colitis; Wild Type Mouse; clinical application; cytokine; in vivo; insight; intestinal epithelium; non-receptor type 7 protein-tyrosine phosphatase; novel; novel diagnostics; overexpression; prevent; receptor; response; statistics

DESCRIPTION (provided by applicant): Increased intestinal permeability plays a crucial role in a number of chronic intestinal inflammatory conditions including Type 1 Diabetes (T1D), celiac disease, as well as Crohn's disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD). More than 1.4 million Americans suffer from IBD. While the exact cause(s) of IBD are unknown, there is considerable evidence that a permeability defect in the intestinal epithelial layer plays a major role in the development of IBD. The intestinal epithelial lining is a single layer of cells that forms the interface between the bactera that reside in the intestine (intestinal microbiota), and the rest of the body. During inflammation the epithelium is exposed to high levels of inflammatory mediators such as interferon-g (IFNg). These mediators activate signaling pathways that alter various functions of the epithelium, such as barrier maintenance. Termination of these signals is mediated largely by the activity of phosphatases. One such phosphatase, protein tyrosine phosphatase non-receptor type 2 (PTPN2), negatively regulates IFNg signaling in non-epithelial cells. However, little is known about the function of PTPN2 in the intestinal epithelium. Recently, single nucleotide polymorphisms (SNP) in the PTPN2 gene have been identified as a genetic marker associated with Crohn's disease, UC, T1D and celiac disease. Thus, these diseases share a common gene association and an elevation in intestinal permeability. We have recently identified a completely novel involvement of PTPN2 in the regulation of epithelial barrier function. Therefore, the specific objectives of this proposal are to understand the role of PTPN2 in regulating intestinal barrier function, and to identify how PTPN2 may be involved in the pathogenesis of chronic intestinal inflammatory diseases. This will be addressed in three specific aims. Aim 1 will investigate how PTPN2 modulates inflammation-induced intestinal barrier dysfunction by determining how PTPN2 restricts intestinal epithelial barrier dysfunction caused by inflammatory cytokines. Aim 2 will identify how the expression, activity and cellular localization of PTPN2 are regulated by inflammatory cytokines. Aim 3 will identify how PTPN2 regulates intestinal permeability in vivo using PTPN2-deficient mice. Expected Outcomes & Impact: These studies will provide fundamental insights into the role of PTPN2 in the regulation of intestinal barrier function, the effect of inflammatory mediators on PTPN2 expression and activity, and the functional consequences of a loss of PTPN2 on epithelial cytokine signaling. On a broader scale, we will identify a unifying link for a gene (PTPN2) and a pathophysiological phenomenon (increased intestinal permeability) that are both fundamentally involved in CD, UC, Type 1 diabetes and celiac disease. These studies may also identify new diagnostic and treatment approaches for IBD patients expressing a PTPN2 SNP.

描述（由申请人提供）：肠通透性增加在许多慢性肠道炎症性疾病中起关键作用，包括1型糖尿病（T1 D）、乳糜泻以及克罗恩病（CD）和溃疡性结肠炎（UC），统称为炎症性肠病（IBD）。超过140万美国人患有IBD。虽然IBD的确切原因尚不清楚，但有相当多的证据表明肠上皮层的通透性缺陷在IBD的发展中起着重要作用。肠上皮衬里是一层细胞，形成了肠道细菌（肠道微生物群）与身体其他部分之间的界面。在炎症期间，上皮暴露于高水平的炎症介质，如干扰素-g（IFNg）。这些介质激活信号通路，改变上皮的各种功能，如屏障维护。这些信号的终止主要由磷酸酶的活性介导。一种这样的磷酸酶，蛋白酪氨酸磷酸酶非受体2型（PTPN 2），负调节非上皮细胞中的IFNg信号传导。然而，PTPN 2在肠上皮中的功能知之甚少。最近，PTPN 2基因中的单核苷酸多态性（SNP）已被鉴定为与克罗恩病、UC、T1 D和乳糜泻相关的遗传标记。因此，这些疾病具有共同的基因关联和肠道通透性升高。我们最近已经确定了一个全新的PTPN 2参与上皮屏障功能的调节。因此，本提案的具体目标是了解PTPN 2在调节肠屏障功能中的作用，并确定PTPN 2如何参与慢性肠道炎症性疾病的发病机制。这将通过三个具体目标来解决。目的1通过研究PTPN 2如何抑制炎性细胞因子引起的肠上皮屏障功能障碍，探讨PTPN 2如何调节炎症诱导的肠屏障功能障碍。目的2：研究炎症因子对PTPN 2表达、活性和细胞定位的调控。目的3将使用PTPN 2缺陷小鼠来确定PTPN 2如何在体内调节肠通透性。预期成果和影响：这些研究将为PTPN 2在肠屏障功能调节中的作用、炎症介质对PTPN 2表达和活性的影响以及PTPN 2缺失对上皮细胞因子信号传导的功能后果提供基本见解。在更广泛的范围内，我们将确定一个基因（PTPN 2）和一个病理生理现象（增加肠道通透性）的统一联系，这两个都是从根本上参与CD，UC，1型糖尿病和乳糜泻。这些研究还可以为表达PTPN 2 SNP的IBD患者确定新的诊断和治疗方法。