A novel role for PTPN2 in Intestinal Barrier Regulation

总结/摘要 受损的肠屏障功能和肠道微生物的改变是导致 许多自身炎性疾病如炎性肠病（IBD）、乳糜泻和1型糖尿病（Type 1 糖尿病，影响约2400万美国人（www.niehs.nih.gov）。遗传因素对这些疾病的影响 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， 酪氨酸磷酸酶非受体2（PTPN 2）基因。此外，PTPN 2被确定为主要的 在组成性缺乏Ptpn 2的小鼠中，我们 确定了肠道微生物群种群的实质性变化， 小鼠粘附侵袭性E. coli（AIEC）。这种小鼠AIEC能够定殖小鼠肠道，加剧 结肠炎发作，并延迟结肠炎的恢复。此外，我们现在报告PTPN 2损失损害了Paneth 在维持肠粘膜微生物稳态中具有关键作用的细胞。我们还发现， 上皮PTPN 2缺失降低潘氏细胞抗菌肽表达，并增加对 病原体感染因此，我们假设PTPN 2作为一种“微生物调节剂”，通过调节先天性 上皮细胞的防御机制，以保护肠道免受细菌“生态失调”，包括扩张 与疾病相关的致病菌AIEC的定殖。本提案的目标是确定 PTPN 2活性的丧失如何破坏i）潘氏细胞抗微生物特性;以及ii）PTPN 2如何调节 上皮抗微生物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加我们对分子基础的更广泛理解： 其中宿主因素保持肠道屏障和微生物体内平衡，并导致新的 在IBD等疾病中恢复宿主-微生物关系的方法和目标。

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.