Investigation of the Carcinogenic Effects of Bactericidal Antibiotics in the Gut

杀菌抗生素在肠道中的致癌作用研究

• 批准号: 10314216
• 负责人: Woojung Shin
• 金额: $ 8.93万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314216
• 关键词: 16S ribosomal RNA sequencing; Animal Model; Antibiotics; Antineoplastic Agents; Atlas of Cancer Mortality in the United States; Atlases; Autologous; Bioinformatics; Biological Models; Biomechanics; Biometry; Cancer Biology; Cancer Model; Cancer Patient; Cells; Coculture Techniques; Colitis associated colorectal cancer; Colorectal Cancer; Complex; Databases; Development; Disease; Disease model; Engineering; Epithelial; Etiology; Experimental Models; Genome; Genomics; Goals; Heterogeneity; Human; Immune; In Vitro; Individual; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Investigation; Learning; Maintenance; Malignant Neoplasms; Maps; Microfluidics; Modeling; Molecular; Molecular Profiling; Organoids; Oxygen; Pathogenicity; Pathologic; Patients; Phase; Research; Research Project Grants; Resolution; Role; Technology; Training; anti-cancer therapeutic; bactericide; base; bioinformatics tool; carcinogenesis; carcinogenicity; colitis associated cancer; combinatorial; fecal microbiome; genetic variant; gut microbiome; high resolution imaging; host microbiome; inflammatory disease of the intestine; inflammatory milieu; innovation; interest; intestinal barrier; intestinal epithelium; microbial signature; microbiome; microbiome research; multiple omics; novel; organ on a chip; response; single cell analysis; single-cell RNA sequencing; spatiotemporal; transcriptome; transcriptomics

Project Summary/Abstract Colitis-associated cancer (CAC) refers to the pathological transition from inflammatory bowel disease (IBD) to colorectal cancer (CRC). Burgeoning evidence suggests that the abnormal intercellular crosstalk between the gut microbiome and inflammatory host cells is highly associated with the development of CAC. Thus, mapping the microbial signature and epithelial plasticity in response to the host-microbiome intercellular crosstalk is critical to mechanistically decipher the role of gut microbiome on the CAC pathogenicity. However, current animal models neither reflect the heterogeneous genetic variants in CAC patients nor quantitatively visualize host- microbiome molecular crosstalk in a spatiotemporal manner. In vitro co-culture models lack the long-term stability to perform a longitudinal host-microbiome study that is necessary to investigate the pathological intercellular crosstalk. Hence, developing a patient-specific CAC model that can quantitatively assess the cellular and molecular signature of host-microbiome crosstalk is a critical unmet need to map the pathological host-gut microbiome crosstalk and unravel their cause vs. consequence in CAC. The long-term goal of the outlined research is to develop transformative and implementable engineered cancer model systems that encompass cancer-microbiome crosstalk. In the F99 phase of this proposed research, a patient-specific CAC-on-a-chip model will be developed by utilizing a cutting-edge human organ-on-a-chip technology. The effects of gut microbiome in the development of CAC will be investigated using this model system. In the K00 phase, single- cell analysis and multi-omics approach will be incorporated into the personalized CAC model for a higher resolution and comprehensive study of the underlying molecular and cellular mechanism of the defined host- microbiome intercellular interactions. By mapping crosstalk between cancer and microbiome, complicated cancer pathobiology will be dissected and manipulated to answer the pressing questions.

项目摘要/摘要 结肠炎相关癌症（CAC）是指从炎症性肠病（IBD）到病理过渡到 结直肠癌（CRC）。新兴的证据表明，在 肠道微生物组和炎症宿主细胞与CAC的发展高度相关。因此，映射 响应宿主 - 微生物组间串扰的微生物特征和上皮可塑性至关重要 机械地破译肠道微生物组对CAC致病性的作用。但是，目前的动物 模型既不能反映CAC患者的异质遗传变异，也不反映宿主的定量可视化 - 微生物组分子串扰以时空方式。体外共培养模型缺乏长期稳定性 进行纵向宿主 - 微生物组研究，这对于研究病理间细胞间是必不可少的 相声。因此，开发一种患者特异性的CAC模型，该模型可以定量评估细胞和 宿主 - 微生物组串扰的分子特征是绘制病理宿主ut的至关重要的需求 微生物组串扰并揭示其原因与CAC的后果。概述的长期目标 研究是为了开发涵盖的变革性和可实施的工程癌症模型系统 癌症 - 微生物组串扰。在这项拟议研究的F99阶段，患者特定的CAC-ON-A-CHIP 模型将通过使用尖端的人体器官芯片技术来开发。肠的影响 将使用此模型系统研究CAC开发中的微生物组。在K00阶段，单个 细胞分析和多词方法将纳入个性化的CAC模型，以提高 对定义宿主的潜在分子和细胞机制的分辨率和综合研究 微生物组间相互作用。通过在癌症和微生物组之间绘制串扰，复杂 癌症病理生物学将被解剖并操纵以回答紧迫的问题。