A comprehensive platform for novel therapy development from the microbiome

微生物组新疗法开发的综合平台

基本信息

批准号：
10206118
负责人：
Curtis Huttenhower
金额：
$ 153.28万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206118
关键词：
Anti-Inflammatory Agents Automobile Driving Bioinformatics Biological Cell Line Cell model Cell physiology Cells Clinical Colorectal Colorectal Cancer Communities Country Data Data Analyses Data Coordinating Center Data Set Development Diabetes Mellitus Digestive System Disorders Discipline Disease model Documentation Drug Targeting Ecosystem Education and Outreach Elements Environment Exercise Functional disorder Gastroenterology Gastrointestinal Diseases Gastrointestinal tract structure Gene Cluster Generations Genetic Risk Gnotobiotic Health Home Human Human Microbiome Human body Immune system Immunity Immunologics Immunology In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Institutes Interleukin-10 Intervention Lead Link Mammalian Cell Maryland Meta-Analysis Metabolic Metabolite Interaction Microbe Molecular Monitor Mus Obesity Pathogenesis Pathway interactions Peptides Phenotype Physiology Population Proteins Protocols documentation Public Health Schools Publishing Research Personnel Resources Sampling Screening Result Signaling Molecule System Systems Biology TNF gene Technology Therapeutic Tissue Model Training Translations Universities Validation Virus Work base clinical center cohort community based participatory research computerized tools cytokine data resource drug development experience gastrointestinal gene product gut microbiome gut microbiota host microbiota in vivo microbial microbial community microbiome microbiome components microbiome research microbiome therapeutics microorganism mouse model novel novel therapeutics pre-clinical prevent response screening small molecule therapy development tool web portal

项目摘要

The gut microbiota is closely linked with many gastrointestinal disorders, including inflammatory bowel diseases (IBD), diabetes, and colorectal cancer. However, many of the molecular mechanisms by which gut microorganisms and their metabolic products perturb host immunity are not yet understood. Both live cell and microbially-derived small molecule interventions have proven to prevent or ameliorate GI inflammation, but to a large degree, the therapeutic potential of targeted components of the microbiome has not yet been realized. In response to RFA-DK-15-012, we thus propose a “community research resource of identified members of the microbiome and factors they elaborate which modulate human physiology or pathophysiology related to... digestive diseases.” The Human Microbial Bioactives Resource (HMBR) will provide a comprehensive platform for discovery, validation, and early-stage translation of novel therapeutics derived from the microbiome: 1. An efficient end-to-end sampling and multi’omic profiling system for the host and microbiota in gastrointestinal disease. 2. Data from thousands of IBD microbiomes and tens of thousands of gut microbiome profiles, spanning dozens of datasets and meta-analyzing multiple countries, cohorts, and clinical centers. 3. Prioritized potentially bioactive elements of the gut microbiome in IBD, including A) microbial species and strains, B) microbial gene products (proteins, secreted peptides, biosynthetic gene clusters, etc.), and C) small molecules (e.g. metabolites or signaling molecules). 4. Screens for high-priority bioactives in vitro using mammalian cell and tissue models to characterize potential mechanisms of action and identify host-microbe-metabolite interactions. 5. Phenotypic readouts (cell population, cellular function-based, and preclinical IBD models) for successful bioactives in conventional and gnotobiotic mice to assess activity in vivo. 6. All HMBR data, protocols, computational tools, microbial isolates, compounds, cell lines, mice, screening results, and training material provided to the community through a unified web-based portal. 7. Exercising the resource with a driving biological application by verifying and characterizing novel modulators of the IL-10 anti-inflammatory and TNFα pro-inflammatory responses. This resource will be developed in the context of the Broad Institute, a leader in gut microbiome profiling and analysis in IBD; the Harvard School of Public Health, home to a rigorously monitored gnotobiotic mouse facility; and the University of Maryland, which currently supports the largest human microbiome resource worldwide in the form of the Human Microbiome Project 1 and 2 Data Coordinating Centers. Through this combination of investigators, environments, resources, and biological applications, we will establish and provide to the community the first platform of its kind for end-to-end microbiome therapeutic discovery and validation.

肠道菌群与许多胃肠道疾病紧密相关，包括炎症肠疾病（IBD），糖尿病和大肠癌。但是，许多分子机制微生物及其代谢产物的驱动宿主免疫尚不清楚。都活细胞和事实证明，微生物衍生的小分子干预措施可以预防或改善胃肠道注射，但尚未实现大大程度的，靶向成分的治疗潜力尚未实现。为了回应RFA-DK-15-012，我们提出了“确定成员的社区研究资源微生物组及其详细的因素，该因素调节了与... 消化疾病。”人类微生物生物活性资源（HMBR）将提供一个全面的平台用于发现，验证和早期阶段的新疗法的早期翻译，这些新疗法源自微生物组： 1。用于宿主的有效端到端采样和多'杂种分析系统和微生物群胃肠道疾病。 2。来自成千上万的IBD微生物组和成千上万的肠道微生物组轮廓的数据，数十个数据集和荟萃分析的多个国家，人群和临床中心。 3。优先考虑IBD肠道微生物组的潜在生物活性元素，包括a）微生物物种菌株，b）微生物基因产物（蛋白质，分泌的肽，生物合成基因簇等）， c）小分子（例如代谢产物或信号分子）。 4。使用哺乳动物细胞和组织模型在体外进行高优先性生物活性剂的筛选以表征作用的潜在机制并识别宿主 - 微生物 - 金代谢物的相互作用。 5。表型读数（细胞种群，基于细胞功能和临床前IBD模型）成功常规和gnotobiotic小鼠中的生物活性剂在体内评估活性。 6。所有HMBR数据，协议，计算工具，微生物分离株，化合物，细胞系，小鼠，筛选结果以及通过基于Web的门户提供给社区的培训材料。 7.通过验证和表征新颖的驾驶生物学应用来行使资源 IL-10抗炎和TNFα促炎反应的调节剂。该资源将在Broad Institute的背景下开发，肠道微生物组分析和 IBD分析；哈佛大学公共卫生学院，受到严格监测的gnotobiotic小鼠设施的所在地；马里兰大学目前支持全球最大的人类微生物组资源人类微生物组项目1和2数据协调中心的形式。通过这种组合调查人员，环境，资源和生物应用，我们将建立并提供社区是端到端微生物组治疗发现和验证的第一个同类平台。