Chemosensory tuft cells and intestinal homeostasis

项目摘要 上皮细胞形成了一个物理和生化屏障，以抵御大量的微生物栖息在 内脏上皮细胞分泌粘液和抗菌肽增强屏障功能， 塑造微生物群的组成。肠上皮细胞还监测管腔微生物， 将信息传递给潜在的免疫细胞以形成粘膜免疫。在本集体内部 上皮细胞有六个专门的细胞亚群，包括簇细胞。以前，簇绒的功能 细胞是未知的，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， 粘膜免疫毛簇细胞识别寄生虫的机制基础知之甚少， 受体和微生物激动剂都是未知的。为了弥补这一知识差距，本提案 将建立在我们观察到的毛簇细胞利用味觉化学感受来响应寄生虫的基础上 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 确定刺激毛丛细胞味觉化学感受的微生物激动剂。使用下一代 测序和gnotobiotic小鼠，这项研究将解开寄生虫改变的作用， 寄生虫及其产物直接刺激簇细胞的微生物组。该项目将产生 有价值的信息之间的具体相互作用簇细胞受体和它们的激动剂，从而 扩大了对味觉受体作为新型肠道微生物识别受体的理解。 簇细胞和味觉化学感觉是肠道中微生物检测的基本新形式， 代表了开发针对肠道炎性疾病的未来疗法的有前途的领域。在 此外，从本建议书中获得的数据、培训和知识对我继续 发展成为独立调查员。

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.