Chemosensory tuft cells and intestinal homeostasis

项目摘要 上皮细胞形成了一种物理和生化屏障，抵御大量栖息的微生物 我的直觉。上皮细胞分泌粘液和抗菌肽增强屏障功能 塑造微生物区系的组成。肠上皮细胞也监测管腔微生物和 将信息传递给潜在的免疫细胞，以塑造粘膜免疫。在集体内部 上皮细胞有六种特殊的细胞亚群，包括簇状细胞。以前，绒毛的功能是 直到我们的小组和另外两个人报告了它们在寄生虫反应中的作用和 粘膜免疫。丛生细胞识别寄生虫的机制基础还知之甚少，如 受体和微生物激动剂都是未知的。为了弥合这一知识差距，这项提议 将建立在我们观察到的丛生细胞利用味觉化学感觉来对寄生虫做出反应的基础上 感染。首先，我们将确定检测寄生虫的味觉化学感受器。同时，我们 确定刺激丛生细胞味觉化学感觉的微生物激动剂。使用下一代 测序和灵知菌小鼠，这项研究将解开寄生虫改变的作用 来自寄生虫及其产物对丛生细胞的直接刺激的微生物群。这个项目将会产生效益 关于簇状细胞受体及其激动剂之间特定相互作用的有价值的信息 扩大味觉受体作为新型肠道微生物识别受体的认识。 丛生细胞和味觉化学感觉是肠道和肠道中微生物检测的根本新形式 代表了未来开发针对肠炎性疾病的治疗方法的一个很有前途的领域。在……里面 此外，从这份计划书中获得的数据、培训和知识对我继续 发展成为一名独立的调查员。

Project Summary Epithelial cells form a physical and biochemical barrier against the vast number of microbes inhabiting the gut. Secretion of mucus and antimicrobial peptides by epithelial cells enhance barrier function and shape the composition of the microbiota. Intestinal epithelial cells also monitor lumenal microbes and transmit information to underlying immune cells to shape mucosal immunity. Within the collective epithelium there are six specialized subsets of cells, including tuft cells. Previously, the function of tuft cells was unknown until our group and two others reported their role in parasite response and mucosal immunity. The mechanistic basis of parasite recognition by tuft cells is poorly understood, as both the receptors and microbial agonists are unknown. To close this knowledge gap, this proposal will build on our observation that tuft cells utilize taste-chemosensation to respond to parasite infections. First, we will identify the taste-chemosensory receptors that detect parasites. In parallel we determine the microbial agonists that stimulate tuft cell taste chemosensation. Using next-generation sequencing and gnotobiotic mice, this study will disentangle the role of the parasite-altered microbiome from direct stimulation of tuft cells by parasites and their products. This project will yield valuable information on specific interactions between tuft cell receptors and their agonists thereby expanding the understanding of taste receptors as novel intestinal microbial recognition receptors. Tuft cells and taste-chemosensation are fundamentally new form of microbial detection in the gut and represent a promising area to develop future therapies targeting intestinal inflammatory disease. In addition the data, training, and knowledge obtained from this proposal are critical for my continued development as an independent investigator.