Microbial regulation of intestinal tuft cell homeostasis

蠕虫感染和过敏性疾病影响全球数十亿人。虽然诱导2型 免疫反应是对抗蠕虫病原体所必需的，不适当的2型免疫触发器 炎症和过敏性疾病。因此，提高了对控制2型糖尿病的机制的理解， 需要免疫反应。肠道微生物群持续影响免疫反应， 研究表明，微生物群衍生的因素会抑制2型免疫。肠丛细胞是 特化上皮细胞对于感知管腔信号和启动下游2型免疫至关重要， 应答我的初步数据表明，微生物群调节簇细胞的稳态和簇细胞依赖性 肠道中的2型免疫反应。本提案中概述的研究将直接测试（i）肠干细胞如何 细胞指导簇细胞分化，和（ii）细菌如何影响簇细胞依赖的2型免疫。 总的来说，这些研究将为微生物群如何指导肠道上皮细胞提供新的见解。 分化，以指导肠道免疫反应，并将指导新的微生物群为基础的方法， 调查和治疗2型肠道疾病。 我的职业目标是使自己成为一名成功的研究微生物调节的肠道 疾病为了实现这一目标，我在本申请中建议剖析 微生物群、上皮细胞分化和粘膜免疫应答。我将特别关注 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型驱动的鼠疾病模型，3）上皮发育和人肠 类器官和4）染色质和单细胞分析。我的导师，阿伦哈特博士和威尔斯博士，沿着 辛辛那提儿童医院的特殊科学和知识环境将使我能够利用 现代，创新的方法在我的研究，并与顶级研究人员合作。在接下来的五年里， 我完全期望我的背景，结合我申请中概述的职业发展计划， 将使我能够成功地执行拟议的项目。我将接受的指导和培训将使我能够 我成功地过渡到一个独立的研究生涯，朝着根本性的进步， 肠道免疫，以及用于调查微生物群敏感性疾病的创新和有针对性的战略。

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.