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.

项目摘要人类微生物组中的细菌产生了一个复杂的生物活性小分子池与对健康和疾病中人类生物学的影响有关，但是这些分子的作用机理保持不确定。该建议建立在微生物组衍生的小分子的初步数据的基础上继发性胆汁酸性岩性酸（LCA）诱导展开的蛋白质反应（UPR），一种信号传导响应内质网（ER）应力的途径。该观察结果链接了微生物组衍生的小分子到宿主细胞生物学的基本方面。在此提案中，申请人试图将此观察结果带入机械级别使用三个完整的目标。在AIM 1中，LCA介导的UPR的后果激活将在肝稳态和损伤的物理模型中定义。在AIM 2中，分子 LCA诱导UPR的机制将使用ER深入监测的组合进行解剖功能，化学和遗传扰动，以探测推定信号通路和接收器的作用。在AIM 3中，胆汁酸的UPR诱导范围较宽，无论是单独还是组合，都将是使用高通量测定法和动物模型进行评估。总之，这项工作将通过微生物组衍生的小分子建立UPR诱导的分子基础。 UPR的失调隐含在代谢性疾病，神经退行性疾病和多种形式中癌症。这项工作可能会为生物标志物和理论策略的发展提供信息疾病。更广泛地，这项工作将提供蓝图，以定义微生物组的小分子通过影响基本细胞生物学过程来形成宿主生物学。哈佛医学院在合作和多学科的生物医学研究中拥有世界领导者环境和包含有关显微镜，基因组学和蛋白质组学的尖端设施，这些设施将支持拟议的研究。共同发起人Marco Jost博士和Wade Harper博士是研究主人的专家 - 微生物组相互作用和调节蛋白质量，并提供完整的技术专业知识和心理观点。拟议研究的完成将直接支持申请人的培训目标，包括培训微生物组生物学，系统遗传学和疾病的动物模型以及支持学术职业的技能的发展。