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

基本信息

批准号：
10558636
负责人：
Woojung Shin
金额：
$ 9.67万
依托单位：
HARVARD UNIVERSITY
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：
2021-02-01 至 2023-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10558636
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 Coupling Databases Development Disease Disease model Engineering Epithelium 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 Postdoctoral Fellow Research Research Project Grants Resolution Role Technology Training Visualization anti-cancer therapeutic bactericide bioinformatics tool cancer complication carcinogenesis carcinogenicity colitis associated cancer combinatorial fecal microbiome genetic variant gut inflammation gut microbiome high resolution imaging host microbiome 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

项目摘要

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.

项目概要/摘要结肠炎相关癌（CAC）是指从炎症性肠病（IBD）到结肠炎的病理转变。结直肠癌（CRC）。越来越多的证据表明，细胞之间的异常细胞间串扰肠道微生物组和炎症宿主细胞与 CAC 的发生高度相关。因此，映射响应宿主微生物组细胞间串扰的微生物特征和上皮可塑性至关重要从机械角度解读肠道微生物组对 CAC 致病性的作用。然而，目前的动物模型既不能反映 CAC 患者的异质遗传变异，也不能定量地可视化宿主微生物组分子以时空方式串扰。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，这对于研究病理性细胞间质是必要的相声。因此，开发一种患者特异性 CAC 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性宿主-肠道图谱的关键未满足需求微生物组串扰并揭示其在 CAC 中的原因与后果。所概述的长期目标研究旨在开发变革性且可实施的工程癌症模型系统，其中包括癌症-微生物组串扰。在这项拟议研究的 F99 阶段，患者特异性 CAC 芯片该模型将利用尖端的人体器官芯片技术开发。肠道的影响将使用该模型系统研究 CAC 发展中的微生物组。在K00阶段，单细胞分析和多组学方法将被纳入个性化 CAC 模型中，以获得更高的结果解析和全面研究特定宿主的潜在分子和细胞机制微生物组细胞间相互作用。通过绘制癌症和微生物组之间的串扰图，复杂的癌症病理学将被剖析和操纵，以回答紧迫的问题。