Microbe dependent mechanisms that antagonize intestinal injury repair

拮抗肠道损伤修复的微生物依赖性机制

基本信息

批准号：
10748588
负责人：
Kevin Newhall
金额：
$ 5.27万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748588
关键词：
Adopted Affect Automobile Driving Biopsy Bone Marrow Candida albicans Cell Line Cells Chemicals Chronic Colon Complement Crohn&apos s disease Cytology Data Disease Disparity Effector Cell Event Food Additives Future Genetic Screening Germination Goals Histoplasmosis Hyphae Immune Evasion Immune response Impaired wound healing Impairment In Vitro Individual Infection Inflammatory Injury Interferon Type I Intestines Macrophage Macrophage Activation Mechanics Methods Microbe Modeling Molecular Morphology Mucous Membrane Mus Mycoses Pathogenesis Pathogenicity Pathway interactions Patients Pattern recognition receptor Phagocytosis Phagolysosome Phase Phenotype Play Predisposition Production RANTES Reproduction spores Research Role Signal Transduction Signaling Molecule Stains Stress TNF gene Testing Tissues Transmission Electron Microscopy Tuberculosis Ulcer Variant Work Yeasts antagonist cell type chronic infection chronic inflammatory disease cytokine data visualization fitness gut microbiome healing immunopathology in vivo in vivo Model injury and repair intestinal injury member microbial microorganism mouse model mutant new therapeutic target pathogen repaired response therapeutic development wound healing

项目摘要

PROJECT SUMMARY Debaryomyces hansenii is a fungal member of the gut microbiome and is present within inflamed regions of the intestine in Crohn Disease patients. Patient-derived strains of D. hansenii prolong wound healing in mouse chemical and mechanical intestinal injury models. Mechanisms of pathogenicity of D. hansenii are not well understood, though macrophages are a key effector cell type in the delayed wound healing phenotype. The objective of the proposed work is to define mechanisms of innate host response to D. hansenii using in vitro macrophage models and define microbial mechanisms of impaired wound repair using in vivo models of intestinal injury. Our preliminary data visualizing phagocytosed D. hansenii with transmission electron microscopy and cytological staining demonstrate certain macrophages phagocytose and are unable to clear D. hansenii. Macrophages that do not clear D. hansenii also do not produce TNF-α in response to D. hansenii. In aim 1, I test the hypothesis that TNF-α supports macrophages clearance of phagocytosed D. hansenii and identify the pattern recognition receptors responsible for TNF-α production. In aim 2, I examine microbial morphologic-transitions as an immune evasion mechanism in vitro and in vivo. My preliminary data suggest that vegetative D. hansenii yeast induce more potent pro-inflammatory cytokine production than spores of D. hansenii, and spores persist within macrophage cell lines in vitro. This project will define microbial mechanisms that permit D. hansenii persistence within the intestine and antagonism of injury repair. Successful completion of these aims will define mechanisms of host-response to D. hansenii and microbial-evasion of macrophage clearance that will lead the identification of novel therapeutic targets for treating the subset of Crohn Disease patients with tissue associated D. hansenii.

项目摘要 Debaryomyces Hanseneii是肠道微生物组的真菌成员，存在于发炎的区域内克罗恩病患者的肠。 D. hansenii的患者衍生菌株延长了小鼠的伤口愈合化学和机械肠损伤模型。 D. hanseneii的致病性机制不好理解齿，尽管巨噬细胞是延迟伤口愈合表型中的关键效应细胞类型。拟议工作的目的是定义先天宿主对D. hansenii的响应的机制。体内使用体内的体外巨噬细胞模型并定义伤口修复受损的微生物机制肠损伤的模型。我们的初步数据可视化吞噬的D. hanseneii与传播电子显微镜和细胞学染色表明某些巨噬细胞吞噬剂，并且无法清除D. Hansenii。尚不清楚D. hansenii的巨噬细胞也不会产生TNF-α以响应D。 Hansenii。在AIM 1中，我检验了以下假设：TNF-α支持吞噬的巨噬细胞清除。 Hanseneii并确定负责TNF-α产生的模式识别受体。在AIM 2中，我检查了微生物形态转变是体外和体内的免疫进化机制。我的初步数据表明，与孢子相比，营养性D. hansenii酵母诱导更多潜在的促炎细胞因子产生 D. hansenii的体外，孢子在巨噬细胞细胞系中持续存在。该项目将定义微生物允许在肠道修复的肠道和拮抗作用中允许D. hansenii持久性的机制。成功的这些目的的完成将定义宿主反应的机制，对hansenii和微生物抗态的机制巨噬细胞清除率将领导鉴定新的治疗靶标，以治疗克罗恩的子集与组织相关的疾病患者。