Role of the complement C3a receptor on immune and non immune intestinal barrier functions and microbiota in colorectal cancer development

补体 C3a 受体对结直肠癌发展中免疫和非免疫肠道屏障功能和微生物群的作用

• 批准号: 10667620
• 负责人: Silvia Guglietta
• 金额: $ 34.83万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667620
• 关键词: APC gene; Affect; Anaphylatoxins; Anti-Bacterial Agents; Anti-Inflammatory Agents; ApcMin/+ mice; Automobile Driving; Bioinformatics; Biological Assay; Biology; Bone Marrow; C3AR1 gene; Cells; Characteristics; Chimera organism; Coculture Techniques; Colon; Colon Carcinoma; Colonic Neoplasms; Colonic inflammation; Colorectal Cancer; Communication; Complement; Complement 3a; Complex; Cytometry; Data; Data Set; Development; Down-Regulation; Environment; Epidemiology; Epithelium; Equilibrium; Event; Functional disorder; Gastrointestinal tract structure; Gatekeeping; Health; Human; Image; Immune; Immune response; Immune system; Inflammation; Inflammatory; Inherited; Intestines; Invasive Lesion; Investigation; Lesion; Link; Measures; Methylation; Microbiology; Mining; Minority; Modeling; Molecular; Mucosal Immune Responses; Mucous Membrane; Mus; Mutation; Natural Immunity; Organoids; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Process; Production; Property; Research Personnel; Role; Seminal; Small Intestines; Specimen; Testing; Work; cancer initiation; cell type; cohort; colorectal cancer prevention; complement C3a receptor; complement system; cytokine; dimensional analysis; dysbiosis; experimental study; fecal transplantation; follow-up; high dimensionality; immune cell infiltrate; immune function; intestinal barrier; intestinal epithelium; intestinal homeostasis; intestinal tumorigenesis; mesenteric lymph node; microbial; microbiota; monolayer; mouse model; multidisciplinary; novel; prevent; receptor; response; tumor; tumor microenvironment; tumorigenesis; tumorigenic

While it was initially believed that only a minority of CRC are driven by inflammation, studies showing that treatment with anti-inflammatory medications may prevent or delay the development of CRC in hereditary and sporadic cases, clearly identify inflammation as a key driver in the development and progression of all types of CRC. Yet, it is still unclear what are the mechanisms that in the complex intestinal environment contribute to the activation of the inflammatory pathways that initiate CRC. The intestine holds a delicate balance between host protection and control of excessive inflammation, and we posit that a dysregulated communication between the epithelial and the immune component of the intestinal barrier may link a sub-acute state of inflammation and CRC initiation. The complement system is emerging as an important player in the gastrointestinal tract. Specifically, the complement anaphylatoxin C3a and its receptor, C3aR, regulate the immune and epithelial compartments in the intestine and exert antibacterial properties. By mining publicly available datasets, we found that C3aR is down-regulated in patients with CRC and the fact that this down-regulation occurs already in stage 1 tumors, suggests that it may be an early event during CRC development. By crossing C3aR-/- mice with the APCMin/+ mice, that carry a mutation in the apc gene, similarly to the majority of human CRC, we showed that C3aR is protective in CRC. Indeed, while in APCMin/+ mice tumors mostly developed in the small intestine, in APCMin/+/C3aR-/- mice tumorigenesis dramatically shifted almost exclusively to the colon. We also found intestinal barrier dysfunction and microbial dysbiosis in mice lacking C3aR, suggesting that C3aR may be a novel gatekeeper in intestinal homeostasis. However, it is currently unknown how C3aR contributes to CRC development. We hypothesize that loss of C3aR causes intestinal barrier dysfunction by affecting the communication between epithelial and immune cells. This then leads to development of microbiota-driven inflammatory immune responses that promote the development of CRC. To test this hypothesis we propose: 1) to investigate how loss of C3aR affects the epithelial component of the intestinal barrier and the communication with the immune cells; 2) To investigate the contribution of C3aR on immune, non immune cell types, and microbiota to CRC development; 3) To investigate the C3aR status in human pre-invasive lesions and CRC. Bone marrow chimera in combination with single cell high dimensional analysis of immune infiltrates using mass cytometry and REAPseq will determine the contribution of C3aR on immune and non immune cells to colon inflammation and CRC development and progression. We will assess how C3aR down-regulation affects human CRC and survival by using human specimens from our well characterized patient cohorts. As loss of C3aR represents an early event during CRC, identifying the mechanisms linking loss of C3aR to the development of CRC will not only further our understanding of CRC but is highly significant for the prevention of CRC.

虽然最初认为只有少数CRC是受炎症驱动的，但研究表明 用抗炎药物治疗可能会阻止或延迟遗传性CRC的发展 零星的病例，清楚地识别出炎症是所有类型的开发和发展的关键驱动力 CRC。然而，尚不清楚复杂肠道环境中有什么贡献的机制是什么 启动CRC的炎症途径的激活。 肠道在宿主保护和控制过度炎症之间保持了微妙的平衡，我们 认为肠上皮和免疫成分之间的通信失调 障碍物可能会连接炎症和CRC启动的亚急性状态。补充系统正在出现 胃肠道的重要参与者。具体而言，补体过敏毒素C3A及其受体， C3AR，调节肠和抗菌特性中的免疫和上皮室。经过 开采公开可用的数据集，我们发现C3AR在CRC患者中被下调，事实是 这种下调已经发生在第1阶段肿瘤中，表明这可能是CRC期间的早期事件 发展。通过将C3AR - / - 小鼠与APCMIN/+小鼠跨过APC基因中的突变 对于大多数人CRC而言，我们表明C3AR在CRC中具有保护性。确实，在apcmin/+小鼠肿瘤中 大多数在小肠中开发，apcmin/+/c3ar - / - 小鼠肿瘤发生急剧转移几乎转移 独家到结肠。我们还发现缺乏的小鼠肠屏障功能障碍和微生物营养不良 C3AR，暗示C3AR可能是肠内稳态中的新型守门人。但是，目前是 C3AR如何为CRC开发做出贡献。 我们假设C3AR的损失通过影响 上皮和免疫细胞。然后，这导致了微生物群驱动的炎症免疫的发展 促进CRC发展的反应。为了检验这一假设，我们提出： 1）调查C3AR的损失如何影响肠屏障的上皮成分和 与免疫细胞通信； 2）研究C3AR对免疫，非免疫细胞的贡献 类型，以及CRC开发的微生物群； 3）研究人类侵入性病变中的C3AR状态 和CRC。骨髓嵌合体与单细胞的高尺寸分析免疫浸润 使用质量细胞仪和REAPSEQ将确定C3AR对免疫和非免疫细胞的贡献 结肠炎症和CRC的发育和进展。我们将评估C3AR下调如何影响 人类CRC和生存通过使用我们特征良好的患者队列中的人类标本。作为损失 C3AR代表CRC期间的一个早期事件，确定将C3AR损失与开发联系起来的机制 CRC不仅将进一步了解我们对CRC的理解，而且对于预防CRC非常重要。