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Establishing the feasibility of editing the human gut microbiome

Establishing the feasibility of editing the human gut microbiome
建立编辑人类肠道微生物组的可行性
批准号:
10621772
负责人:
Peter James Turnbaugh
金额:
$40.38万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-08-01 至 2025-05-31

项目摘要

项目成果

Peter James Turnbaugh的其他基金

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中文摘要
翻译
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英文摘要
PROJECT SUMMARY Definitive links between the remarkable inter-individual genotypic variation in the human microbiome and disease are still limited due to the lack of generalizable methods to precisely remove microbial genes from complex microbial communities in situ. Not only would such a technology help transform the microbiome field from a descriptive to a mechanistic discipline, but it would also have immediate clinical applications. The goal of this Focused Technology Research and Development (PAR-19-253) application is to establish a generalizable toolkit to program the endogenous CRISPR-Cas systems in human gut bacteria to knockout genes of interest with unprecedented precision. CRISPR-Cas is a bacterial immune system, composed of RNA-guided nucleases, that protect the cell against bacteriophage and other foreign DNA. Endogenous CRISPR-Cas systems can be programmed to target their own genomic DNA using custom guide RNAs (gRNAs) homologous to a gene of interest. As an initial proof-of-principle we will target a single gut bacterial gene that we discovered is responsible for the inactivation of the cardiac drug digoxin, but if successful this approach could be readily extended to the numerous bacterial species that have now been implicated in host physiology and the predisposition to and treatment of disease. We will pursue the following Specific Aims: (Aim I) the functional validation of a novel CRISPR-Cas system in Eggerthella lenta, a prevalent gut Actinobacterium with multiple links to metabolism and microbial pathogenesis; (Aim II) the isolation and rebooting of bacteriophages that infect human gut bacteria; and (Aim III) the engineering of bacteriophage to program an endogenous gut bacterial CRISPR-Cas system. Our long-term goal is to establish the first modular tools for engineering the gut microbiome to delete one gene, combinations of genes, or even entire metabolic pathways. Importantly, by focusing on endogenous CRISPR-Cas systems, we anticipate that along the way we will uncover basic insights into the diversity, regulation, and function of these systems, with broad implications for our understanding of the complex interactions between bacteriophages, their bacterial hosts, and their shared mammalian habitat. While our early results provide support for feasibility, this high-risk, high- reward technology development plan would have broad implications for the study of microbial communities and host-microbiome interactions while bringing the promise of microbiome-based therapeutics within reach.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1128/mbio.01573-23
发表时间: 2023-10-31
期刊: mBio
影响因子: 6.4
作者: []
通讯作者:
Microbiome single cell atlases generated with a commercial instrument.
使用商业仪器生成的微生物组单细胞图谱。
DOI: 10.21203/rs.3.rs-3253785/v1
发表时间: 2023
期刊: Research square
影响因子: --
作者: [Abate,Adam, Li,Xiangpeng, Xu,Linfeng, Demaree,Benjamin, Noecker,Cecilia, Bisanz,Jordan, Weisgerber,Daniel, Modavi,Cyrus, Turnbaugh,Peter]
通讯作者: Turnbaugh,Peter
Variety of Fruit and Vegetables and Alcohol Intake are Associated with Gut Microbial Species and Gene Abundance in Colorectal Cancer Survivors.
多种果实,蔬菜和酒精摄入量与结直肠癌幸存者中的肠道微生物物种以及基因丰度有关。
DOI: 10.1016/j.ajcnut.2023.07.011
发表时间: 2023-09
期刊: The American journal of clinical nutrition
影响因子: --
作者: []
通讯作者:
Metabolism of cancer chemotherapeutics by the human gut microbiome
Host-microbiome interactions shape the metabolic effects of ketogenic diets
Establishing the feasibility of editing the human gut microbiome
Host-microbiome interactions shape the metabolic effects of ketogenic diets