Chemosensory tuft cells and intestinal homeostasis

化学感应簇细胞和肠道稳态

• 批准号: 9886236
• 负责人: Michael R Howitt
• 金额: $ 15.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886236
• 关键词: 16S ribosomal RNA sequencing; Affect; Agonist; Area; Biochemical; Biology; Cell Communication; Cells; Cellular biology; Data; Detection; Development; Enterocytes; Enteroendocrine Cell; Epithelial; Epithelial Cells; Epithelium; Future; Genetic Transcription; Germ-Free; Gnotobiotic; Goblet Cells; Grant; Homeostasis; Hypersensitivity; Immune; Immune response; Immune system; Immunity; Impairment; In Vitro; Infection; Inflammatory Bowel Diseases; Intestinal parasite; Intestines; Knowledge; Lead; Measures; Mentorship; Microbe; Monitor; Mucosal Immunity; Mucous body substance; Mus; Paneth Cells; Parasites; Parasitic infection; Physiological; Physiology; Reaction; Receptor Cell; Reporting; Research Personnel; Role; Sentinel; Series; Shapes; Signal Transduction; Small Intestines; Taste Buds; Taste Perception; Testing; Training; antimicrobial peptide; cell type; chronic inflammatory disease; cytokine; design; experience; gut microbiota; host microbiota; in vivo; inflammatory disease of the intestine; insight; intestinal epithelium; intestinal homeostasis; member; microbial; microbiome; microbiome alteration; microbiota; next generation sequencing; novel; novel therapeutics; receptor; response; sensor; targeted treatment

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.

项目概要 上皮细胞形成物理和生化屏障，抵抗大量栖息的微生物 肠道。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和 将信息传递给底层免疫细胞以形成粘膜免疫。集体内 上皮有六种特殊的细胞亚群，包括簇细胞。以前，簇绒的功能 直到我们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。簇细胞识别寄生虫的机制基础尚不清楚，因为 受体和微生物激动剂都是未知的。为了缩小这一知识差距，本提案 将建立在我们的观察基础上，即簇细胞利用味觉化学感觉来响应寄生虫 感染。首先，我们将识别检测寄生虫的味觉化学感应受体。与此同时，我们 确定刺激簇细胞味觉化学感觉的微生物激动剂。使用下一代 测序和限生小鼠，这项研究将解开寄生虫改变的作用 来自寄生虫及其产物直接刺激簇细胞的微生物组。该项目将产生 关于簇细胞受体与其激动剂之间的特定相互作用的有价值的信息 扩大对味觉受体作为新型肠道微生物识别受体的理解。 簇状细胞和味觉化学感觉是肠道微生物检测的全新形式。 代表了开发针对肠道炎症疾病的未来疗法的一个有前景的领域。在 此外，从该提案中获得的数据、培训和知识对于我继续 作为一名独立调查员的发展。