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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.

项目概要汉逊德巴利酵母是肠道微生物组的真菌成员，存在于肠道发炎区域。克罗恩病患者的肠道。源自患者的汉逊汉森氏菌菌株可延长小鼠伤口愈合时间化学和机械性肠道损伤模型。汉逊石线虫的致病机制尚不明确尽管巨噬细胞是伤口愈合延迟表型中的关键效应细胞类型，但这一点已被理解。这拟议工作的目标是定义汉逊汉森氏菌的先天宿主反应机制体外巨噬细胞模型并使用体内定义受损伤口修复的微生物机制肠道损伤模型。我们的初步数据显示了吞噬汉逊汉森氏菌的传播情况电子显微镜和细胞学染色显示某些巨噬细胞具有吞噬作用，但不能清除汉逊汉逊氏菌。不清除汉逊巨噬细胞的巨噬细胞也不会产生响应汉逊巨噬细胞的 TNF-α。汉逊尼。在目标 1 中，我检验了 TNF-α 支持巨噬细胞清除吞噬 D 的假设。汉逊酵母并鉴定负责 TNF-α 产生的模式识别受体。在目标 2 中，我检查微生物形态转变作为体外和体内的免疫逃避机制。我的初步数据表明汉逊酵母营养体比孢子诱导更有效的促炎细胞因子产生汉逊汉森氏菌，并且孢子在体外持续存在于巨噬细胞系内。该项目将定义微生物允许汉逊汉森氏菌在肠道内持续存在并拮抗损伤修复的机制。成功的这些目标的完成将确定宿主对汉逊汉森氏菌的反应和微生物逃避的机制巨噬细胞清除将导致识别治疗克罗恩病亚型的新治疗靶点疾病患者具有与汉逊汉森氏菌相关的组织。