Microbial regulation of intestinal tuft cell homeostasis

肠道簇细胞稳态的微生物调节

• 批准号: 10638381
• 负责人: Emily M. Eshleman
• 金额: $ 14.18万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638381
• 关键词: Allergic; Allergic Disease; Allergic inflammation; Area; Butyrates; Calibration; Cell Count; Cell Differentiation process; Cell Lineage; Cells; Chromatin; Chronic; Collaborations; Data; Development; Development Plans; Disease; Disease model; Environment; Epigenetic Process; Epithelial Cells; Epithelium; Fibrosis; Food Hypersensitivity; Gastrointestinal tract structure; Gnotobiotic; Goals; HDAC3 gene; Health; Helminths; Histone Deacetylase Inhibitor; Homeostasis; Human; Hypersensitivity; Immune System Diseases; Immune response; Immunity; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Intervention; Intestinal Diseases; Intestines; Link; Mediating; Mentors; Mentorship; Metagenomics; Microbe; Modeling; Modernization; Molecular; Mucosal Immune Responses; Mus; Organoids; Outcome Study; Parasitic infection; Pathogenesis; Pathway interactions; Pediatric Hospitals; Production; Regulation; Research; Research Personnel; Role; Signal Transduction; Specialized Epithelial Cell; Stimulus; Testing; Training; Transgenic Mice; Transgenic Organisms; Translating; Work; career; career development; commensal bacteria; cytokine; design; fighting; gut inflammation; gut microbiota; helminth infection; host microbiota; immunoregulation; improved; inhibitor; innovation; insight; intestinal epithelium; microbial; microbiota; mouse model; novel; novel strategies; novel therapeutic intervention; pathogen; prevent; response; single cell analysis; single-cell RNA sequencing; stem cells; tissue repair; tool

Helminth infections and allergic diseases impact billions of individuals worldwide. While induction of type 2 immune responses are necessary for combatting helminth pathogens, inappropriate type 2 immunity triggers inflammatory and allergic conditions. Therefore, improved understanding of mechanisms that control type 2 immune responses are needed. The intestinal microbiota continually influence immune responses, and several studies have demonstrated that microbiota-derived factors dampen type 2 immunity. Intestinal tuft cells are specialized epithelial cells that are essential for sensing luminal signals and initiating downstream type 2 immune responses. My preliminary data indicate that the microbiota regulate tuft cell homeostasis and tuft cell-dependent type 2 immune responses in the intestine. Studies outlined in this proposal will directly test (i) how intestinal stem cells instruct tuft cell differentiation, and (ii) how commensal bacteria impact tuft cell-dependent type 2 immunity. Collectively, these studies will provide new insights into how the microbiota direct intestinal epithelial differentiation to instruct intestinal immune responses, and will guide novel microbiota-based approaches for investigating and treating type 2-driven intestinal diseases. My career goal is to establish myself as a successful investigator studying microbiota-regulated intestinal diseases. To progress towards this goal, I propose in this application to dissect interactions between the microbiota, epithelial cell differentiation, and mucosal immune responses. I will specifically concentrate on developing expertise in four new areas that will facilitate my transition to independence: 1) gnotobiotics and metagenomics, 2) type 2-driven murine disease models, 3) epithelial development and human intestinal organoids, and 4) chromatin and single cell analyses. My mentors, Dr. Alenghat and Dr. Wells, along with the exceptional scientific and intellectual environment at Cincinnati Children’s Hospital will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. Over the next five years, I fully anticipate that my background, in conjunction with the career development plan outlined in my application, will allow me to successfully carry out the proposed project. The mentoring and training I will receive will enable me to successfully transition to an independent research career directed towards fundamental advances in intestinal immunity, as well as innovative and targeted strategies for investigating microbiota-sensitive diseases.

蠕虫感染和过敏性疾病会影响全球数十亿个人。而诱导2型 免疫反应对于打击蠕虫病原体是必需的，不适当 炎症和过敏性条件。因此，改善了控制2型机制的理解 需要免疫反应。肠道菌群不断影响免疫反应，有几个 研究表明，微生物群衍生的因子该死的2型免疫培养基。肠簇细胞是 专门的上皮细胞，对于传感腔信号和下游2型免疫启动至关重要 回答。我的初步数据表明，微生物群调节簇细胞稳态和簇细胞依赖性 肠道中的2型免疫回报。该提案中概述的研究将直接检验（i）肠干 细胞指导簇簇细胞分化，以及（ii）共生细菌如何影响簇状细胞依赖性2型免疫培养。 总的来说，这些研究将为微生物群如何直接肠上皮提供新的见解 分化以指导肠道免疫调查，并将指导基于微生物群的新方法 研究和治疗2型肠道疾病。 我的职业目标是将自己确立为研究微生物群调节的肠道的成功研究者 疾病。为了朝着这个目标迈进，我建议在此应用中剖析 微生物群，上皮细胞分化和粘膜免疫反应。我将专门专注于 在四个新领域发展专业知识，这将有助于我向独立过渡：1）Gnotobiotics和 宏基因组学，2）2型2驱动的鼠类疾病模型，3）上皮发育和人类肠道 器官，4）染色质和单细胞分析。我的导师Alenghat博士和Wells博士以及 辛辛那提儿童医院的卓越科学和智力环境将使我能够利用 在我的研究中，现代，创新的方法与顶级研究人员合作。在接下来的五年中， 我完全期望我的背景与我的申请中概述的职业发展计划一起 将允许我成功执行拟议的项目。我将获得的心理和培训将启用 我成功地过渡到针对基本进步的独立研究职业 肠道免疫，以及研究微生物群敏感性疾病的创新和有针对性的策略。