Determine the role of TLR1 signaling in chronic inflammation and colorectal cance

描述（由申请人提供）：慢性炎症与结直肠癌（CRC）的发生之间存在联系。这在炎症性肠病（IBD）患者的CRC数量增加以及慢性炎症患者的癌症严重程度中都可以看到。我们发现Toll样受体1（TLR1）是一种重要的先天性受体，在调节粘膜免疫应答中起重要作用。TLR1的缺乏导致免疫和上皮细胞反应失调，导致慢性炎症，改变肠道微生物组和激活参与诱变的途径。重要的是，这些研究也有翻译应用，因为我们发现TLR1中的突变，消除了表面表达和信号传导，与儿科IBD患者相关。此外，具有破坏的TLR1信号传导的患者还具有更严重的疾病、对抗TNF治疗的应答丧失和生长缺陷。拟议工作的目标将研究缺乏TLR1信号传导如何影响CRC模型中的肠道微生物组和肠上皮细胞。具体来说，我们将研究TLR1缺陷小鼠的慢性炎症是否会将肠道微生物组改变为肿瘤促进表型，以及改变的微生物组和TLR1信号传导对免疫系统和上皮细胞的影响。这些研究的结果对理解先天免疫信号失调如何影响慢性炎症和癌症进展具有重要意义。此外，它将提供对TLR1信号传导中断的患者是否更容易患慢性炎症和CRC的理解，从而允许早期预防，治疗和潜在的治疗。

DESCRIPTION (provided by applicant): There is a link between chronic inflammation and the development of colorectal cancers (CRC). This is seen in both the increase in number of CRC in patients with inflammatory bowel disease (IBD), as well as in the severity of cancer in patients with chronic inflammation. We have found that Toll-like receptor 1 (TLR1) is an important innate receptor in regulating mucosal immune responses. The absence of TLR1 causes dysregulated immune and epithelial cell responses leading to chronic inflammation, altered commensal microbiome and activation of pathways involved in mutagenesis. Importantly, these studies also have translational application as we have found that a mutation in TLR1, which abrogates surface expression and signaling, is associated with pediatric IBD patients. Further, patients with disrupted TLR1 signaling also have a more severe disease, loss of response to anti-TNF therapy and defects in growth. The goals of the proposed work will examine how deficient TLR1 signaling impacts the commensal microbiome and intestinal epithelial cells in a model of CRC. Specifically, we will examine whether the chronic inflammation in TLR1-deficient mice alters the commensal microbiome to a tumor promoting phenotype and the impact that the altered microbiome and TLR1 signaling have on the immune system and the epithelium. The results of these studies have important consequences on the understanding of how dysregulated innate immune signaling can impact chronic inflammation and cancer progression. Further, it will provide an understanding of whether patients with disrupted TLR1 signaling are more susceptible to chronic inflammation and CRC allowing early prevention, treatment and potential therapies.