A Novel Role for PTPN2 in Intestinal Epithelial Barrier Regulation

PTPN2 在肠上皮屏障调节中的新作用

基本信息

批准号：
10752105
负责人：
Declan McCole
金额：
$ 59.65万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-05 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752105
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肠道菌群失调的关键因素。许多自身炎症性疾病，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）这些疾病的遗传因素。包括与蛋白质中功能丧失的单核苷酸多态性 (SNP) 的关联增加此外，PTPN2 被确定为主要的酪氨酸磷酸酶非受体 2 型基因。对多个患者群体的微生物组成的影响。在本质上缺乏 Ptpn2 的小鼠中，我们发现肠道微生物群发生了重大变化，这种变化突出表现为一种新型微生物丰度的增加小鼠粘附侵袭性大肠杆菌 (AIEC) 该小鼠 AIEC 能够定植于小鼠肠道，并加剧。此外，我们现在报告 PTPN2 缺失会损害 Paneth。我们还发现，这些细胞在维持肠粘膜微生物稳态方面发挥着关键作用。上皮 PTPN2 缺失会降低潘氏细胞抗菌肽表达，并增加对细菌的敏感性因此，我们勇敢地认为 PTPN2 通过调节先天性来充当“微生物调节剂”。上皮细胞的防御机制，保护肠道免受细菌“生态失调”的影响，包括扩张疾病相关病原体 AIEC 的定植和定植本提案的目标是确定。 PTPN2 活性的丧失如何破坏 i) 潘氏细胞抗菌特性；以及 ii) PTPN2 如何调节上皮抗菌防御和细胞内细菌处理的其他（非潘氏细胞）特征。预期成果和影响：该提案将通过以下方式增进我们对分子基础的更广泛理解哪些宿主因素可以保护肠道屏障和微生物稳态，并导致新的开发在IBD等疾病中恢复宿主-微生物关系的方法和目标。