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: 9384696
• 负责人: Declan McCole
• 金额: $ 50.28万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384696
• 关键词: Active Sites; Address; Affect; American; Apical; Bacteria; Candidate Disease Gene; Cations; Celiac Disease; Cell Line; Cell model; Cells; Chronic; Chronic Disease; Clinical; Crohn' s disease; Defect; Development; Disease; Disease Outcome; Electrolytes; Epithelial; Epithelial Cells; Epithelium; Event; Functional disorder; Funding; Genes; Genetic; Genetic Markers; Hereditary Disease; Human; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interferons; Intestines; JAK1 gene; JAK3 gene; Knockout Mice; Lead; Maintenance; Mediating; Mediator of activation protein; Molecular; Mucositis; Mus; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Organoids; Outcome; Pathogenesis; Pathway interactions; Patients; Permeability; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Property; Protein Tyrosine Phosphatase; Proteins; Regulation; Rest; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Tamoxifen; Testing; Therapeutic; Therapeutic Agents; Tight Junctions; Treatment Efficacy; Ulcerative Colitis; genome wide association study; gut microbiota; inhibitor/antagonist; intestinal epithelium; loss of function; loss of function mutation; macromolecule; mouse model; mutant; novel; novel therapeutics; overexpression; prevent; statistics; therapeutic target; villin

Project Summary 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 cell (IEC) 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 bacteria 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- (IFN). 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 IFN signaling in non-epithelial cells. However, little is known about the function of PTPN2 in the intestinal epithelium. Single nucleotide polymorphisms (SNP) in the PTPN2 gene have been confirmed 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 identified a completely novel involvement of PTPN2 in the regulation of epithelial barrier function. Therefore, the specific objectives of this proposal are to better understand how PTPN2 loss-of-function mutations alter phosphorylation signaling networks impacting upon intestinal barrier function, and if this can be corrected by a clinically-effective therapeutic agent. This will be addressed in three specific aims. Aim 1: Determine the molecular mechanisms causing epithelial barrier defects due to PTPN2 loss of function Aim 2: PTPN2 is a negative regulator of JAK-STAT inflammatory signaling pathways. We will investigate if the JAK inhibitor, Tofacitinib can correct the consequences of PTPN2 loss of function through inhibiting JAK-STAT pathways normally restricted by PTPN2. Aim 3: Identify how loss of PTPN2 phosphatase activity alters its “phospho- interactome” in IEC and how does this impact upon tight junction protein phosphoregulation. Expected Outcomes & Impact: These studies will not only build a more accurate mechanistic understanding of the consequences of loss-of-function PTPN2 mutations for barrier function regulation and associated signaling networks, but will also identify a possible therapeutic approach to resolve these defects.

项目摘要 肠道渗透率提高在许多慢性肠道炎症条件下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）， 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，但有大量证据表明渗透性缺陷 肠上皮细胞（IEC）层在IBD的发展中起主要作用。肠上皮衬里 是单层的细胞，形成了驻留在肠道（肠）中的细菌之间的界面 微生物群）和身体的其余部分。在炎症期间，上皮暴露于高水平 炎症介质，例如干扰素-（IFN）。这些介体激活了改变的信号通路 上皮的各种功能，例如屏障维护。这些信号的终止是介导的 主要是由于磷酸酶的活性。一种这样的磷酸酶，蛋白酪氨酸磷酸酶非受体类型 2（PTPN2），负调控非上皮细胞中的IFN信号传导。但是，关于 PTPN2在肠上皮的功能。 PTPN2基因中的单核苷酸多态性（SNP）具有 我们被确认为与克罗恩病，UC，T1D和腹腔疾病有关的遗传标记。那，这些 疾病具有共同的基因关联和肠渗透性的升高。我们已经确定了 PTPN2完全新颖地参与了上皮屏障功能的调节。因此，具体 该提案的目标是更好地了解PTPN2功能丧失突变如何改变 影响肠道屏障功能的磷酸化信号网络，如果可以通过 临床有效的治疗剂。这将以三个具体目标解决。目标1：确定 由于PTPN2的功能损失AIM 2：PTPN2是A的分子机制，导致上皮屏障缺陷。 JAK-STAT炎症信号通路的负调节剂。我们将调查JAK抑制剂是否， tofacitinib可以通过抑制JAK-STAT途径来纠正PTPN2功能丧失的后果 通常受PTPN2的限制。 AIM 3：确定PTPN2磷酸酶活性的丧失如何改变其磷酸 IEC中的Interactome”以及这对紧密连接蛋白磷酸调节的影响如何。 成果和影响：这些研究不仅会建立对该研究的更准确的机械理解 功能丧失PTPN2突变的后果对屏障功能调节和相关信号传导的后果 网络，但还将确定一种解决这些缺陷的可能治疗方法。