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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.

项目摘要/摘要结肠炎相关癌(CAC)是指炎症性肠病(IBD)向结直肠癌(CRC)越来越多的证据表明，细胞间的异常串扰肠道微生物群和炎性宿主细胞与CAC的发生发展密切相关。因此，映射微生物特征和上皮可塑性对宿主-微生物组细胞间串扰的响应是至关重要的。从机制上破译肠道微生物群在CAC致病中的作用。然而，目前的动物模型既没有反映CAC患者的异质性遗传变异，也没有定量地可视化宿主- 微生物组在时空上的分子串扰。体外共培养模型缺乏长期稳定性进行纵向的宿主-微生物组研究，这是研究病理细胞间的必要的相声。因此，开发一种针对患者的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描绘病理性宿主-肠道的一个关键的未得到满足的需求微生物群串扰及其在CAC中的原因和后果。规划的长期目标研究是开发具有变革性和可实施性的癌症工程模型系统，该系统包括癌症-微生物群的串音。在这项拟议研究的F99阶段，针对患者的芯片上CAC 该模型将利用尖端的人体芯片器官技术进行开发。肠道的影响将利用该模型系统研究CAC发展过程中的微生物群。在K00阶段，单人- 细胞分析和多组学方法将被纳入到个性化CAC模型中，以获得更高的对确定的宿主的潜在分子和细胞机制的解析和全面研究微生物组细胞间的相互作用。通过绘制癌症和微生物群之间的串扰图，复杂癌症病理生物学将被解剖和操纵，以回答紧迫的问题。