Linking a prominent gut microbiome-derived metabolite to host proteostasis

将一种重要的肠道微生物组衍生代谢物与宿主蛋白质稳态联系起来

基本信息

批准号：
10923047
负责人：
Nolan Kenji Kwaisun Maier
金额：
$ 0.25万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10923047
关键词：
Academic support Acids Affect Animal Disease Models Animal Model Autoimmune Diseases Bacteria Bile Acids Biological Assay Biological Process Biology Biomedical Research Biosensor Cells Cellular biology Chemicals Circulation Complex Correlative Study Data Development Diabetes Mellitus Disease Disease susceptibility Endoplasmic Reticulum Environment Exposure to Foundations Genetic Genetic Models Genomics Goals Growth Health Hepatocyte Homeostasis Human Human Biology Human Cell Line Human Microbiome Individual Injury Lead Link Lithocholic Acid Liver Liver diseases Malignant Neoplasms Malignant neoplasm of liver Measures Mediating Mentors Metabolic Diseases Microscopy Molecular Monitor Mus Nerve Degeneration Neurodegenerative Disorders Observational Study Pathway interactions Physiological Physiology Proteins Proteomics Published Comment Regulation Research Resistance Role Secondary to Severities Shapes Signal Pathway Signal Transduction Technical Expertise Therapeutic Therapeutic Intervention Training Variant Work biological adaptation to stress biomarker development biomarker identification career design endoplasmic reticulum stress experimental study feeding genome-wide gut microbes gut microbiome high throughput screening host microbiome human disease human microbiota improved insight liver injury medical schools microbiome microbiome composition multidisciplinary nervous system disorder novel marker physiologic model programs proteostasis receptor response skills small molecule stressor therapeutically effective

项目摘要

Project Summary Bacteria in the human microbiome produce a complex pool of bioactive small molecules that have been associated with effects on human biology in health and disease, but the mechanisms of action of these molecules remain largely undefined. This proposal builds on preliminary data that a microbiome-derived small molecule, the secondary bile acid lithocholic acid (LCA), induces the Unfolded Protein Response (UPR), a signaling pathway that responds to endoplasmic reticulum (ER) stress. This observation links a microbiome-derived small molecule to a basic aspect of host cell biology. In this proposal, the applicant seeks to bring this observation to the mechanistic level using three complementary aims. In Aim 1, the consequences of LCA-mediated UPR activation will be defined in physiological models of liver homeostasis and injury. In Aim 2, the molecular mechanism by which LCA induces the UPR will be dissected using a combination of in-depth monitoring of ER function and chemical and genetic perturbations to probe the roles of putative signaling pathways and receptors. In Aim 3, the broader scope of UPR induction by bile acids, both individually and in combinations, will be assessed using high-throughput assays and animal models. Together, this work will establish the molecular basis of UPR induction by microbiome-derived small molecules. Dysregulation of the UPR is implicated in metabolic disorders, neurodegenerative disease, and multiple forms of cancer. Thus, this work may inform the development of biomarkers and therapeutic strategies for such diseases. More broadly, this work will provide a blueprint to define how small molecules from the microbiome shape host biology by impacting fundamental cell biological processes. Harvard Medical School houses world leaders in biomedical research in a collaborative and multidisciplinary environment and contains cutting-edge facilities for microscopy, genomics, and proteomics that will support the proposed research. The co-sponsors Dr. Marco Jost and Dr. Wade Harper are experts in studying host- microbiome interactions and regulation proteostasis, respectively, and provide complementary technical expertise and mentoring viewpoints. Completion of the proposed research will directly support the applicant’s training goals, including training in microbiome biology, systematic genetics, and animal models of disease and growth of skills to support an academic career.

项目概要人类微生物组中的细菌产生一系列复杂的生物活性小分子，这些小分子已被与对人类健康和疾病生物学的影响有关，但这些分子的作用机制该提议基于微生物组衍生的小分子的初步数据，次级胆汁酸石胆酸 (LCA) 诱导未折叠蛋白反应 (UPR)，这是一种信号传导响应内质网（ER）应激的通路这一观察结果将微生物组衍生的小分子联系起来。在该提案中，申请人试图将这一观察结果应用到宿主细胞生物学的一个基本方面。使用三个互补目标的机械层面在目标 1 中，LCA 介导的 UPR 的后果。激活将在肝脏稳态和损伤的生理模型中定义。在目标 2 中，分子。 LCA 诱导 UPR 的机制将通过结合 ER 的深入监测来剖析功能以及化学和遗传扰动来探测假定的信号通路和受体的作用。在目标 3 中，胆汁酸单独或组合诱导 UPR 的范围更广。使用高通量测定和动物模型进行评估。总之，这项工作将建立微生物组衍生小分子诱导 UPR 的分子基础。 UPR 失调与代谢紊乱、神经退行性疾病和多种形式有关因此，这项工作可能会为此类生物标志物和治疗策略的开发提供信息。更广泛地说，这项工作将提供一个蓝图来定义微生物组中的小分子。通过影响基本的细胞生物过程来塑造宿主生物学。哈佛医学院拥有世界领先的生物医学研究合作和多学科研究机构环境并包含用于显微镜、基因组学和蛋白质组学的尖端设施，这些设施将支持共同发起人 Marco Jost 博士和 Wade Harper 博士是研究宿主的专家。微生物组相互作用和调节蛋白质稳态，并提供补充技术专业知识和指导观点的完成将直接支持申请人的研究。培训目标，包括微生物组生物学、系统遗传学和疾病动物模型的培训支持学术生涯的技能增长。