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

确定 TLR1 信号传导在慢性炎症和结直肠癌中的作用

• 批准号: 8620553
• 负责人: R William DePaolo
• 金额: $ 21.47万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620553
• 关键词: Anti-Tumor Necrosis Factor Therapy; Apoptosis; Behavior; Cells; Childhood; Chronic; Colon Carcinoma; Colorectal; Colorectal Cancer; Communication; Data; Defect; Dendritic Cells; Development; Disease; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Figs - dietary; Gastroenteritis; Gastrointestinal tract structure; Germ-Free; Goals; Growth; Healed; Homeostasis; Immune; Immune Cell Activation; Immune response; Immune system; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Interleukin-6; Intestines; Link; Malignant Neoplasms; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mus; Mutagenesis; Mutation; Oncogene Activation; Pathway interactions; Patients; Phenotype; Play; Population; Prevalence; Prevention; Process; Receptor Signaling; Regulation; Research; Resolution; Risk; Role; STAT3 gene; Severities; Signal Transduction; Single Nucleotide Polymorphism; Surface; T cell response; Therapeutic; Toll-Like Receptor 1; Toll-like receptors; Transplantation; Work; cancer risk; carcinogenesis; commensal microbes; healing; injury and repair; intestinal epithelium; microbial; microbiome; next generation sequencing; prevent; public health relevance; receptor; response; response to injury; tissue regeneration; translational study; tumor; tumor progression; tumorigenesis

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.

描述(申请人提供)：慢性炎症与结直肠癌(CRC)的发展之间存在联系。这既体现在炎症性肠病(IBD)患者结直肠癌数量的增加，也体现在慢性炎症患者癌症的严重性上。我们发现Toll样受体1(TLR1)是调节粘膜免疫反应的一种重要的先天受体。TLR1的缺失导致免疫和上皮细胞反应失调，导致慢性炎症、共生微生物群改变和参与突变的通路激活。重要的是，这些研究也有翻译应用，因为我们发现TLR1的一个突变，它取消了表面表达和信号，与儿童IBD患者相关。此外，TLR1信号紊乱的患者还会有更严重的疾病，对抗肿瘤坏死因子治疗失去反应，以及生长缺陷。这项拟议工作的目标将检验TLR1信号缺陷如何影响结直肠癌模型中的共生微生物群和肠道上皮细胞。具体地说，我们将检查TLR1缺陷小鼠的慢性炎症是否会将共生微生物群改变为促进肿瘤的表型，以及改变的微生物群和TLR1信号对免疫系统和上皮细胞的影响。这些研究的结果对理解调节失调的先天免疫信号如何影响慢性炎症和癌症进展具有重要影响。此外，它还将提供对TLR1信号中断的患者是否更容易患慢性炎症和结直肠癌的理解，从而允许早期预防、治疗和潜在的治疗方法。