Treating colon cancer by regulating intestinal immunity through microbial metabolism

通过微生物代谢调节肠道免疫治疗结肠癌

基本信息

批准号：
10618990
负责人：
Nicholas Arpaia
金额：
$ 55.41万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618990
关键词：
16S ribosomal RNA sequencing Affect Anti-Inflammatory Agents Antibiotics Aryl Hydrocarbon Receptor Bile Acids Butyrates Cancer Model Cell Count Cell Proliferation Cells Chemoprotective Agent Colitis Colitis associated colorectal cancer Colon Colon Carcinoma Colorectal Cancer Data Development Diet Engineered Probiotics Engineering Enzymes Epithelium Escherichia coli Essential Genes Event Gastrointestinal tract structure Genetic Engineering Gnotobiotic Goals Growth Immune Immune Targeting Immune signaling Immune system Immunity Immunotherapeutic agent Immunotherapy Indole-3-Carbinol Inflammatory Bowel Diseases Interleukin-10 Intervention Intestines Knockout Mice Knowledge Link Malignant Neoplasms Mediating Metabolic Metabolism Microbe Modeling Mucosal Immune Responses Mus Mutagenesis Mutation Outcome Oxygen Pathway interactions Plants Population Prevention Probiotics Production Proliferating Receptor Signaling Regulatory T-Lymphocyte Role Serum Signal Pathway Signal Transduction Source Supplementation T-Lymphocyte Techniques Testing Therapeutic Therapeutic Intervention Tissues Tryptophan Volatile Fatty Acids Work anti-cancer cell type chemotherapy colorectal cancer risk colorectal cancer treatment conditional knockout cytokine dextran sulfate sodium induced colitis dietary efficacy evaluation gut microbes gut microbiome gut microbiota immune cell infiltrate immune modulating agents immunological intervention immunoregulation improved in vivo insight intestinal epithelium metabolomics microbial microbiome neoplasm immunotherapy novel promoter protective effect reconstitution response sensor synthetic biology targeted treatment tumor

项目摘要

PROJECT SUMMARY Colorectal cancer (CRC) is profoundly affected by the intestinal immune system and the intestinal microbiome, which can exert both pro- and anti-cancer effects that operate alongside cell-intrinsic mutational events. Immune cells produce reactive molecules and cytokines which contribute to epithelial mutagenesis and proliferation, and immune cells infiltrate developing tumors and influence response to chemotherapy and anti-tumor immunotherapy. Therapeutically modulating the immune system holds potential for transforming CRC outcomes, but such interventions must be precisely targeted to specific signaling pathways, immune cell types and, ideally, delivered locally. One promising source for such precision immunomodulatory targets are metabolites produced by the intestinal microbiome, which have recently been shown to exert powerful effects on specific immune cell types in the intestine. Exploiting the therapeutic potential of microbial metabolites requires: 1) basic knowledge of the diet-microbe-metabolite-immune signaling network, 2) safe and effective means for localized metabolite delivery, and 3) validated targets for defined therapeutic contexts. In this proposal, we will address these three key gaps, with a unifying focus on a key population of anti-inflammatory T cells in the intestine: RORgt+ regulatory T cells (RORgt+ Tregs). In Aim 1, we will dissect the mechanism of a previously unknown microbome-metabolite- immune pathway by which the microbiome and dietary tryptophan regulate intestinal RORgt+ Treg populations. In Aim 2, we will engineer a probiotic strain of E coli to serve as a general platform for localized delivery of therapeutic metabolites; our initial goal will be to boost RORgt+ Tregs by overproducing the short-chain fatty acid butyrate. In Aim3, we will evaluate the efficacy of elevating RORgt+ Tregs (via dietary butyrate) on key outcomes for sporadic vs colitis-associated CRC in vivo. This project will deepen our understanding of metabolic immunoregulation, develop novel probiotic strains for therapeutic metabolite delivery, and evaluate the role of an important anti-inflammatory cell type in CRC.

项目概要结直肠癌（CRC）深受肠道免疫系统和肠道微生物组的影响，它可以发挥与细胞内在突变事件一起作用的促癌和抗癌作用。免疫细胞产生有助于上皮突变和增殖的反应性分子和细胞因子，以及免疫细胞渗透发展中的肿瘤并影响化疗和抗肿瘤的反应免疫疗法。治疗性调节免疫系统有可能改变结直肠癌的结果，但此类干预措施必须精确针对特定的信号传导途径、免疫细胞类型，并且理想情况下，本地交付。这种精确免疫调节靶点的一个有希望的来源是产生的代谢物最近被证明对特定免疫细胞产生强大影响的肠道微生物组肠道内的类型。开发微生物代谢物的治疗潜力需要：1）基础知识饮食-微生物-代谢物-免疫信号网络的组成，2）安全有效的局部代谢物手段交付，以及 3）针对确定的治疗环境验证目标。在本提案中，我们将解决这三个问题关键差距，统一关注肠道中关键的抗炎 T 细胞群：RORgt+ 调节 T 细胞（RORgt+ Tregs）。在目标 1 中，我们将剖析以前未知的微生物组-代谢物-的机制微生物组和饮食色氨酸通过免疫途径调节肠道 RORgt+ Treg 群体。在目标 2 中，我们将设计一种大肠杆菌益生菌菌株，作为本地化递送的通用平台。治疗代谢物；我们最初的目标是通过过量产生短链脂肪酸来增强 RORgt+ Tregs 丁酸盐。在 Aim3 中，我们将评估提升 RORgt+ Tregs（通过饮食丁酸盐）对关键结果的功效体内散发性结直肠癌与结肠炎相关结直肠癌的比较。该项目将加深我们对代谢的理解免疫调节，开发用于治疗代谢物输送的新型益生菌菌株，并评估其作用结直肠癌中重要的抗炎细胞类型。