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: 10522693
• 负责人: Silvia Guglietta
• 金额: $ 36.17万
• 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/10522693
• 关键词: APC gene; Acute; 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; Epithelial; Equilibrium; Event; Functional disorder; Gastrointestinal tract structure; Gatekeeping; Health; Human; Image; Immune; Immune response; Immune system; Inflammation; Inflammatory; Inherited; Intestines; 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; Tumor-infiltrating immune cells; Work; cancer initiation; cancer survival; cell type; cohort; colorectal cancer prevention; complement C3a receptor; complement system; cytokine; dimensional analysis; dysbiosis; experimental study; fecal transplantation; follow-up; high dimensionality; immune function; intestinal barrier; intestinal epithelium; intestinal homeostasis; intestinal tumorigenesis; mesenteric lymph node; microbial; microbiota; monolayer; mouse model; multidisciplinary; novel; prevent; receptor; 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是由炎症引起的，但研究表明， 用抗炎药物治疗可以预防或延缓遗传性和 散发病例，清楚地确定炎症是所有类型的发展和进展的关键驱动因素， 《儿童权利公约》。然而，目前尚不清楚在复杂的肠道环境中， 启动CRC的炎症通路的激活。 肠道在保护宿主和控制过度炎症之间保持着微妙的平衡， 认为肠道上皮和免疫成分之间的通讯失调， 屏障可能将亚急性炎症状态与CRC启动联系起来。补体系统正在出现， 在胃肠道中扮演重要角色。特别是补体过敏毒素C3 a及其受体， C3 aR调节肠道中的免疫和上皮区室并发挥抗菌特性。通过 挖掘公开可用的数据集，我们发现C3 aR在CRC患者中下调， 这种下调已经发生在1期肿瘤中，表明它可能是CRC期间的早期事件 发展通过将C3 aR-/-小鼠与携带apc基因突变的APCMin/+小鼠杂交， 对于大多数人CRC，我们表明C3 aR在CRC中是保护性的。事实上，在APCMin/+小鼠肿瘤中， 大多数发生在小肠，在APCMin/+/C3 aR-/-小鼠中，肿瘤发生几乎 专门针对结肠。我们还发现，缺乏肠道屏障功能障碍和微生物生态失调的小鼠， C3 aR，这表明C3 aR可能是肠道稳态的新守门人。但目前 不知道C3 aR如何促进CRC的发展。 我们假设C3 aR的缺失通过影响肠粘膜与肠上皮细胞之间的通讯而引起肠屏障功能障碍。 上皮细胞和免疫细胞。然后导致微生物群驱动的炎症免疫的发展， 促进《儿童权利公约》发展的对策。为了验证这一假设，我们提出： 1)研究C3 aR的缺失如何影响肠屏障的上皮成分和肠上皮细胞的功能。 研究C3 aR在免疫细胞、非免疫细胞和免疫细胞中的作用 类型和微生物群对CRC发展的影响; 3）研究人类浸润前病变中的C3 aR状态 和CRC。骨髓嵌合体结合单细胞免疫浸润的高维分析 使用质谱细胞术和REAPseq将确定C3 aR对免疫和非免疫细胞的贡献 结肠炎症和CRC的发展和进展。我们将评估C3 aR下调如何影响 通过使用来自我们充分表征的患者队列的人类标本，研究人CRC和存活率。丧失 C3 aR代表CRC期间的早期事件，确定了将C3 aR缺失与CRC发展联系起来的机制。 研究CRC不仅可以加深我们对CRC的认识，而且对CRC的预防也具有重要意义。