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 基因组革命给我们提供了一种关于我们对 肠道微生物群落在疾病中的组成，但我们仍远不了解微生物是如何 基因和途径会影响宿主的健康。虽然大量的研究表明，微生物群与 在疾病状态下，我们对响应疾病相关扰动的微生物基因知之甚少，例如 如炎症或药物治疗，以及这些微生物反应如何促进疾病和药物反应。 缺乏对微生物基因如何响应和促成与疾病相关的干扰的知识限制了我们 能够合理设计微生物群靶向治疗，例如粪便微生物区系移植，活着 生物疗法和小分子微生物抑制剂。我的实验室的长期目标是了解 微生物组有助于全身炎症的消退。R35 NIGMS的总体目标是 米拉的资助是为了支持我的研究项目，重点是破译微生物基因 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。在支持下 在35兰特的米拉赠款中，我的目标是在未来5年内在交叉口建立一个独特的、富有成效的利基市场 通过研究以下关键问题，了解微生物学、遗传学和全身性炎症性疾病 主题：(1)哪些微生物基因对宿主炎症和药物治疗起重要作用；(2) 这些微生物基因随后如何促进宿主炎症，以及(3)靶向特定的药物 微生物基因在宿主炎症的背景下影响肠道微生物的生态和进化。建议数 研究计划寻求通过利用尖端技术和我独特的 计算机科学、基因组学、微生物学、临床免疫学和灵知生物学背景。人类 肠道微生物群与我们“从现在到永恒”在一起，但我们才刚刚开始发现体内的强大力量 它们塑造了微生物群落及其进化。这些变化的微生物遗传基础 炎症和药物治疗并不是很普遍的研究；填补这一基本知识缺口将会带来红利 通过改善目前正在进行的治疗策略的有效性，在未来 炎症性疾病。