From here to eternity: gut microbial response to drug therapy and inflammation

从这里到永恒：肠道微生物对药物治疗和炎症的反应

• 批准号: 10716004
• 负责人: Renuka Rajendra Nayak
• 金额: $ 38.33万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716004
• 关键词: Biological Response Modifier Therapy; Clinical Immunology; Disease; Drug Targeting; Ecology; Evolution; Future; Genes; Genetic; Genetic Determinism; Genomics; Goals; Grant; Health; Human; Inflammation; Inflammatory; Knowledge; Microbe; Microbial Genetics; Microbiology; National Institute of General Medical Sciences; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Productivity; Research; Resolution; Shapes; Technology; Treatment Efficacy; computer science; design; fecal transplantation; gut microbes; gut microbiome; gut microbiota; improved; in vivo; inhibitor; microbial; microbial community; microbiome; new therapeutic target; programs; rational design; response; small molecule; systemic inflammatory response; targeted treatment

ABSTRACT The genomic revolution has provided us with an “embarrassment of riches” with respect to our understanding of the composition of gut microbial communities in disease, but we are still far from understanding how microbial genes and pathways impact host health. While a wealth of studies show that the microbiome is associated with disease states, we know little about the microbial genes that respond to disease-associated perturbations, such as inflammation or drug therapy, and how these microbial responses contribute to disease and drug response. Lack of knowledge of how microbial genes respond and contribute to disease-associated perturbations limits our ability to rationally design microbiome-targeted therapies, such as fecal microbiota transplant, live biotherapeutics, and small molecule microbial inhibitors. My lab’s long-term goal is to understand how the microbiome contributes to the resolution of systemic inflammation. The overall objective of this R35 NIGMS MIRA grant is to support the aspect of my research program focused on deciphering the microbial genetic determinants of responses to inflammation and drug therapy and how these impact the host. With the support of the R35 MIRA grant, over the next 5 years, I aim to establish a unique and productive niche at the intersection of microbiology, genetics, and systemic inflammatory disease by investigating the following key questions / themes: (1) which microbial genes are important for responding to host inflammation and drug treatment, (2) how do these microbial genes subsequently contribute to host inflammation, and (3) can drugs targeting specific microbial genes impact gut microbial ecology and evolution in the setting of host inflammation. The proposed research program seeks to fill these knowledge gaps by harnessing cutting-edge technologies and my unique backgrounds in computer science, genomics, microbiology, clinical immunology, and gnotobiology. The human gut microbiome is with us “from here to eternity” but we are just beginning to uncover the powerful forces in vivo that shape the microbial community and its evolution. The microbial genetic basis of these shifts in the setting of inflammation and drug therapy is not commonly studied; filling this fundamental knowledge gap will pay dividends in the future by improving the efficacy of therapeutic strategies that are currently underway in patients with inflammatory disease.

摘要 基因组革命为我们提供了一个“财富的尴尬”，就我们对基因组的理解而言， 疾病中肠道微生物群落的组成，但我们还远未了解微生物如何 基因和途径影响宿主健康。虽然大量的研究表明，微生物组与 疾病状态，我们对微生物基因对疾病相关扰动的反应知之甚少， 作为炎症或药物治疗，以及这些微生物反应如何有助于疾病和药物反应。 缺乏对微生物基因如何响应和促进疾病相关扰动的知识限制了我们的研究。 合理设计微生物组靶向治疗的能力，如粪便微生物组移植， 生物治疗剂和小分子微生物抑制剂。我实验室的长期目标是了解 微生物组有助于解决全身性炎症。R35 NIGMS的总体目标 MIRA的资助是为了支持我的研究计划，重点是破译微生物的基因 炎症和药物治疗反应的决定因素以及这些因素如何影响宿主。与支撑 的R35 MIRA赠款，在未来5年，我的目标是建立一个独特的和富有成效的利基在交叉点 微生物学，遗传学和全身性炎症性疾病的研究，通过调查以下关键问题/ 主题：（1）哪些微生物基因对响应宿主炎症和药物治疗很重要，（2） 这些微生物基因如何导致宿主炎症，以及（3）药物是否可以靶向特定的 微生物基因影响肠道微生物生态学和宿主炎症环境中的进化。拟议 一项研究计划旨在通过利用尖端技术和我独特的技术来填补这些知识空白。 具有计算机科学、基因组学、微生物学、临床免疫学和gnotobiology的背景。人类 肠道微生物组与我们“从这里到永恒”，但我们才刚刚开始揭示体内的强大力量 塑造了微生物群落及其进化。这些变化的微生物遗传基础， 炎症和药物治疗的研究并不普遍;填补这一基本知识空白将带来回报 在未来，通过提高目前正在进行的治疗策略在患有 炎症性疾病。