Cytokine regulation of intestinal epithelial restitution

项目摘要 炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，是一种慢性炎症性肠病。 胃肠道的炎症性疾病。IBD困扰着美国近150万人。 IBD的确切原因尚不清楚，但一般认为与宿主免疫功能失调有关。 在遗传易感个体中对肠道微生物的反应。肿瘤坏死因子（TNF），a 主要的免疫细胞因子，在疾病过程中具有核心作用。虽然抗TNF治疗是治疗的一部分， 对于许多IBD患者的药物治疗方案，越来越多的证据表明，TNF的完全阻断 对于许多人来说，长期信令是不合适的。例如，大多数接受抗TNF治疗的患者 生物制剂在5年内对治疗无效。我们和其他人已经证明，TNF信号 通过其较少表征的受体TNFR 2，对结肠损伤的修复具有许多有益的功能， 上皮屏障，IBD的一个重要缓解方面，以及对免疫细胞的调节，包括细胞毒性 (CD8+）T淋巴细胞和调节性T细胞。该应用程序将跟踪这些新的观察结果， 探讨TNFR2对CD8+ T细胞和结肠上皮干细胞保护作用的机制 细胞群在结肠损伤和炎症的情况下。具体而言，我们将：1）确定 TNFR2调节结肠炎中CD8+ T细胞致病性的机制，2）阐明TNFR2在结肠炎中的作用， TNFR2在调节CD8+ T细胞亚群及其结肠定位中的作用，以及3）确定TNFR2在CD8+ T细胞亚群及其结肠定位中的作用。 上皮TNFR2对结肠上皮干细胞动力学和粘膜愈合的影响。这些研究将揭示 重要的细胞和分子模式，可能是IBD的病理生理学基础。

PROJECT SUMMARY Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract. IBD afflicts nearly 1.5 million people in the United States. The exact causes of IBD are unknown, but they are thought to generally involve dysregulated host immune responses to commensal microorganisms in genetically susceptible individuals. Tumor necrosis factor (TNF), a major immune cytokine, has a central role in the disease process. While anti-TNF therapies are a part of the medical regimen for many IBD patients, there is mounting evidence that the complete blockade of TNF signaling is not appropriate in the long-term for many. For example, most patients treated with anti-TNF biologics stop responding to the therapy within 5 years. We and others have demonstrated that TNF signaling through its lesser-characterized receptor TNFR2 has many beneficial functions on the repair of the colonic epithelial barrier, a crucial mitigating aspect of IBD, and on the regulation of immune cells including cytotoxic (CD8+) T lymphocytes and regulatory T cells. This application will follow-up on these novel observations to explore the mechanisms that underlie TNFR2's protective effects on CD8+ T cells and colonic epithelial stem cell populations in the setting of colonic injury and inflammation. Specifically, we will: 1) determine the mechanisms by which TNFR2 regulates the pathogenicity of CD8+ T cells in colitis, 2) elucidate the role of TNFR2 in regulation of CD8+ T cell subpopulations and their colonic localization, and 3) define the role of epithelial TNFR2 on colonic epithelial stem cell dynamics and mucosal healing. These studies will reveal important cellular and molecular patterns that may underlie the pathophysiology of IBD.