A novel role for PTPN2 in Intestinal Barrier Regulation

PTPN2 在肠道屏障调节中的新作用

基本信息

批准号：
10906407
负责人：
Declan McCole
金额：
$ 8.48万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10906407
关键词：
Adherent Invasive Escherichia coli Affect American Anti-Bacterial Agents Architecture Autophagocytosis Biological Models Candidate Disease Gene Celiac Disease Cell physiology Cells Chronic Clinical Colitis Data Defect Defense Mechanisms Development Disease Enterocytes Epithelial Cells Epithelium Escherichia coli Infections Event Generations Genes Genetic Goals Goblet Cells Homeostasis Human IL18 gene Immune Infection Inflammatory Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Integration Host Factors Interferons Intestinal Mucosa Intestines Invaded Knockout Mice Large Intestine Microbe Molecular Mucous body substance Mus Outcome Paneth Cells Patients Penetration Permeability Population Predisposition Production Property Protein Tyrosine Phosphatase Recovery Regulation Reporting Rheumatoid Arthritis Risk Role Signal Transduction Single Nucleotide Polymorphism Small Intestines Stimulus Testing Variant antimicrobial antimicrobial peptide autoinflammatory autoinflammatory diseases biological adaptation to stress cell type cohort dysbiosis endoplasmic reticulum stress gut microbiota host-microbe interactions human model in vitro Model in vivo inhibitor interleukin-22 intestinal barrier intestinal epithelium loss of function microbial microbiome composition mouse model novel novel strategies pathobiont pathogen preservation response stem cell biomarkers

项目摘要

SUMMARY/ABSTRACT Compromised intestinal barrier function and alterations in intestinal microbes are critical factors contributing to many autoinflammatory diseases such as Inflammatory Bowel Disease (IBD), celiac disease and Type 1 diabetes, and affect ~24 million Americans (www.niehs.nih.gov). Genetic contributions to these diseases include the increased association with loss-of-function single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene. Moreover, PTPN2 was identified as a major influence on microbiome composition across multiple patient cohorts.In mice constitutively lacking Ptpn2, we identified substantial changes in gut microbiota populations highlighted by increased abundance of a novel mouse adherent-invasive E. coli (AIEC). This mouse AIEC was able to colonize mouse intestine, exacerbate colitis onset, and delay recovery from colitis. Moreover, we now report that PTPN2 loss compromises Paneth cells which have critical roles in preserving intestinal mucosal-microbial homeostasis. We also identify that epithelial PTPN2 deletion reduces Paneth cell antimicrobial peptide expression, and increases susceptibility to pathogen infection. Thus, we hypothesize that PTPN2 serves as a “microbial modulator” by regulating innate defense mechanisms of epithelial cells to protect the intestine against bacterial ‘dysbiosis’, including expansion of, and colonization with, the disease-relevant pathobiont, AIEC. The goals of this proposal are to determine how loss of PTPN2 activity disrupts i) Paneth cell antimicrobial properties; and ii) how does PTPN2 regulate other (non-Paneth cell) features of epithelial antimicrobial defense and intracellular bacterial handling. Expected Outcomes & Impact: This proposal will increase our broader understanding of the molecular basis by which host factors preserve the intestinal barrier and microbial homeostasis, and lead to development of new approaches and targets to restore host-microbe relationships in diseases such as IBD.

摘要/摘要肠道屏障功能受损和肠道微生物的改变是导致的关键因素许多自身炎症性疾病，例如炎症性肠病（IBD），乳糜泻和1型糖尿病，影响约2400万美国人（www.niehs.nih.gov）。对这些疾病的遗传贡献包括增加与功能丧失的单核苷酸多态性（SNP）的关联酪氨酸磷酸酶非受体2型（PTPN2）基因。此外，PTPN2被确定为主要对多个患者队列的微生物组组成的影响。在组成性缺乏PTPN2的小鼠中，我们鉴定出肠道菌群种群的实质变化是由新颖的抽象提出的鼠标粘附的大肠杆菌（AIEC）。这款鼠标AIEC能够殖民鼠标肠，恶化结肠炎发作，延迟从结肠炎中恢复。此外，我们现在报告说PTPN2损失损害了Paneth 在保存肠粘膜微生物稳态方面具有关键作用的细胞。我们还确定上皮PTPN2缺失可降低泛细胞抗菌胡椒的表达，并增加对病原体感染。这是我们假设PTPN2通过调节先天而用作“微生物调节剂” 上皮细胞的防御机制保护肠子免受细菌“营养不良”的影响，包括扩张与疾病相关的病原体，AIEC。该提议的目标是确定 PTPN2活性的丧失如何破坏i）paneth细胞抗菌特性； ii）PTPN2如何调节上皮抗微生物防御和细胞内细菌处理的其他（非木板细胞）特征。预期的结果和影响：该提案将通过哪种宿主因素保留了肠道屏障和微生物稳态，并导致新的恢复IBD等疾病中宿主微生物关系的方法和目标。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis.

DOI：
10.1053/j.gastro.2013.08.054
发表时间：
2013-12
期刊：
Gastroenterology
影响因子：
29.4
作者：
Marchelletta RR;Gareau MG;McCole DF;Okamoto S;Roel E;Klinkenberg R;Guiney DG;Fierer J;Barrett KE
通讯作者：
Barrett KE

Regulation of epithelial barrier function by the inflammatory bowel disease candidate gene, PTPN2.

DOI：
10.1111/j.1749-6632.2012.06522.x
发表时间：
2012-06
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
McCole DF
通讯作者：
McCole DF

IBD candidate genes and intestinal barrier regulation.

DOI：
10.1097/mib.0000000000000090
发表时间：
2014-10
期刊：
Inflammatory bowel diseases
影响因子：
4.9
作者：
McCole DF
通讯作者：
McCole DF

Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation.

DOI：
10.1097/mib.0000000000000297
发表时间：
2015-03
期刊：
Inflammatory bowel diseases
影响因子：
4.9
作者：
Spalinger MR;McCole DF;Rogler G;Scharl M
通讯作者：
Scharl M

Activation of protein tyrosine phosphatase non-receptor type 2 by spermidine exerts anti-inflammatory effects in human THP-1 monocytes and in a mouse model of acute colitis.

DOI：
10.1371/journal.pone.0073703
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Morón B;Spalinger M;Kasper S;Atrott K;Frey-Wagner I;Fried M;McCole DF;Rogler G;Scharl M
通讯作者：
Scharl M