Linking a prominent gut microbiome-derived metabolite to host proteostasis

项目摘要 人体微生物组中的细菌产生一个复杂的生物活性小分子库， 与健康和疾病对人类生物学的影响有关，但这些分子的作用机制 在很大程度上是不确定的。该提议建立在微生物组衍生的小分子的初步数据基础上， 二级胆汁酸石胆酸（LCA）诱导未折叠蛋白反应（UPR），一种信号传导 内质网（ER）应激的反应途径。这一观察结果将微生物组来源的小 分子到宿主细胞生物学的基本方面。在本提案中，申请人试图将这一意见提交给 使用三个互补目标的机械水平。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的机制将结合对ER的深入监测进行剖析。 功能和化学和遗传扰动，以探测推定的信号通路和受体的作用。 在目标3中，胆汁酸单独和联合诱导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的小分子诱导UPR的分子基础。 UPR的失调与代谢紊乱、神经退行性疾病和多种形式的 癌症。因此，这项工作可能会为此类疾病的生物标志物和治疗策略的发展提供信息。 疾病更广泛地说，这项工作将提供一个蓝图，以确定如何从微生物组的小分子 通过影响基本的细胞生物学过程来塑造宿主生物学。 哈佛医学院以合作和多学科的方式拥有世界领先的生物医学研究 环境，并包含先进的设施，显微镜，基因组学和蛋白质组学，将支持 提议的研究。共同发起人Marco Jost博士和Wade哈珀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，并提供互补的技术 专业知识和指导观点。完成拟议的研究将直接支持申请人的 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， 技能的增长，以支持学术生涯。

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.