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Tuft cell heterogeneity in function, lineage, and structure in ileal inflammatory disease

回肠炎症性疾病中簇细胞功能、谱系和结构的异质性

基本信息

批准号：
10463073
负责人：
Ken S Lau
金额：
$ 3.43万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463073
关键词：
Ablation Affect Antigens Architecture Biological Assay Cell Lineage Cells Cellular biology Chemical Models Chemicals Complementary therapies Complex Computer Analysis Country Crohn&apos s disease Cytometry Dependence Developed Countries Diagnosis Disease Disease model Electron Microscopy Enzyme-Linked Immunosorbent Assay Epithelial Fluorescence Genetic Genetic Models Goals Heterogeneity Human Hygiene Ileal Diseases Image Cytometry Immune Immune response Immune system Immunofluorescence Microscopy Incidence Individual Inflammation Inflammatory Inflammatory Bowel Diseases Intestinal Mucosa Intestines Knowledge Microscopy Modeling Mucous Membrane Mus Organ Organoids PTGS2 gene Parasites Parasitic Diseases Parasitic infection Pathway interactions Patients Population Population Heterogeneity Precision therapeutics Research Resolution Rest Role Rosaniline Dyes Sampling Sentinel Small Intestines Sorting - Cell Movement Specimen Stains Structure Structure-Activity Relationship Testing Therapeutic Time Tissues Work cell type cytokine design disorder subtype genetic manipulation helminth infection host microbiome immunoregulation in vivo Model innovation longitudinal analysis microbiome microbiota mouse model multiplexed imaging novel patient stratification response single cell sequencing single-cell RNA sequencing therapeutic target transcription factor translational applications tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Inflammatory Bowel Disease (IBD) and its subtype Crohn’s disease (CD) arise due to a loss of tolerance to environmental antigens in genetically susceptible individuals. Longitudinal analysis has identified an inverse correlation between rates of communicable parasitic diseases and IBD, a phenomenon termed the “hygiene hypothesis.” Tuft cells have recently been identified as a critical component for sensing and responding to parasitic infections. Our lab has recently identified that tuft cells may be heterogeneous in their lineage and function in microbiome response, and specific populations may be critical for mitigating inflammation in ileal inflammatory disease. Here, we propose innovative experimental and computational approaches to dissect the heterogeneity of tuft cell lineage, structure, and function as they relate to regulating immune responses in in vivo models of CD. In aim 1, we will conduct single-cell sequencing, high resolution microscopy, and functional secretory assays to understand lineage-structure-function relationships in different tuft cell populations in mouse and enteroid models. In aim 2, we utilize multiplex imaging, Cytometry Time-of-Flight (CyTOF), and cytokine profiling to probe the downstream tuft-type 2 response network by utilizing several chemical and genetic models of pathway ablation. Through our findings, we aim to make significant contributions to the current understanding of tuft cell biology and epithelial-microbiome crosstalk in the intestine. Ultimately, this research will allow us to diagnose, stratify, and, ultimately, treat patients with IBD and expand the pool of targets in this complex, multifactorial disease.

项目总结/摘要炎症性肠病（IBD）及其亚型克罗恩病（CD）是由于缺乏免疫抑制剂而引起的。遗传易感个体对环境抗原的耐受性纵向分析已经确定了传染性寄生虫病和IBD之间的负相关性，这一现象被称为“卫生假说”簇细胞最近被鉴定为是感应和应对寄生虫感染的关键部件。我们的实验室最近发现簇状细胞在其谱系和微生物组中的功能上可能是异质的，反应，特定人群可能是减轻回肠炎性结肠炎炎症的关键。疾病在这里，我们提出了创新的实验和计算方法来剖析与调节免疫相关簇细胞谱系、结构和功能的异质性在CD的体内模型中的反应。在目标1中，我们将进行单细胞测序，分辨率显微镜和功能性分泌测定，以了解谱系结构功能小鼠和肠模型中不同簇细胞群的关系。在目标2中，多重成像、流式细胞术飞行时间（CyTOF）和细胞因子分析，以探测下游簇2型响应网络，利用几个化学和遗传模型，通路消融通过我们的研究结果，我们的目标是为当前的了解肠道中的簇细胞生物学和上皮-微生物组串扰。最后，这项研究将使我们能够诊断、分层并最终治疗IBD患者，这个复杂的多因素疾病的靶点库。