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）：肠道通透性的提高在许多慢性肠道炎性疾病中起着至关重要的作用，包括1型糖尿病（T1D），腹腔疾病以及克罗恩病（CD）和溃疡性结肠炎（UC），共同称为炎症性肺疾病（IBD）。超过140万美国人患有IBD。尽管IBD的确切原因尚不清楚，但有大量证据表明，肠上皮层中的渗透性缺陷在IBD的发展中起主要作用。肠上皮衬里是单层细胞，形成驻留在肠道（肠道菌群）和身体其余部分的细菌之间的界面。在炎症期间，上皮暴露于高水平的炎症介质（例如Interferon-g）（IFNG）。这些介体激活了改变上皮各种功能的信号通路，例如屏障维持。这些信号的终止主要是由磷酸酶的活性介导的。一种这样的磷酸酶，一种蛋白酪氨酸磷酸酶非受体2型（PTPN2），对非上皮细胞中的IFNG信号进行负调节。然而，关于PTPN2在肠上皮的功能知之甚少。最近，PTPN2基因中的单核苷酸多态性（SNP）已被确定为与克罗恩病，UC，T1D和腹腔疾病相关的遗传标记。因此，这些疾病具有共同的基因缔合和肠道通透性的升高。我们最近确定了PTPN2在调节上皮屏障功能中的完全新颖的参与。因此，该提案的具体目标是了解PTPN2在调节肠道屏障功能中的作用，并确定PTPN2如何参与慢性肠道炎症性疾病的发病机理。这将以三个具体目标解决。 AIM 1将通过确定PTPN2如何限制由炎症细胞因子引起的肠上皮屏障功能障碍来调节PTPN2如何调节炎症诱导的肠道屏障功能障碍。 AIM 2将确定PTPN2的表达，活性和细胞定位如何受炎症细胞因子调节。 AIM 3将确定PTPN2如何使用PTPN2缺陷型小鼠在体内调节肠道通透性。预期结果和影响：这些研究将提供对PTPN2在肠道屏障功能调节中的作用的基本见解，炎症介体对PTPN2表达和活性的影响以及PTPN2丧失PTPN2对上皮细胞因子信号的功能后果。在更广泛的范围内，我们将确定基因（PTPN2）和病理生理现象的统一联系（肠道通透性增加），这些连接从根本上涉及CD，UC，UC，1型糖尿病和乳糜泻。这些研究还可以确定表达PTPN2 SNP的IBD患者的新诊断和治疗方法。