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

• 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
• 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' 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

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 汉逊德巴利酵母是肠道微生物组的真菌成员，并且存在于胃肠道的发炎区域内。 克罗恩病患者的肠道。患者来源的D. Hansenii延长小鼠创伤愈合 化学和机械性肠损伤模型。对D.汉森尼人身体不好 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，但这是可以理解的。的 本研究的目的是明确宿主对D. hansenii用于 体外巨噬细胞模型，并使用体内方法确定受损伤口修复的微生物机制 肠损伤模型。我们的初步数据可视化吞噬D。带传动装置的汉森尼 电子显微镜和细胞学染色显示某些巨噬细胞吞噬， 清除D。汉森尼。不清除D的宏程序。hansenii也不产生TNF-α。 汉森尼。在目的1中，我检验了TNF-α支持巨噬细胞清除吞噬的D. hansenii和识别负责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免疫逃避机制。我的初步数据 提示植物D.汉逊酵母比孢子诱导更有效促炎细胞因子产生 氏盐汉逊氏菌，孢子在体外存留于巨噬细胞系内。该项目将定义微生物 允许D.汉逊杆菌在肠内的持久性和损伤修复的拮抗作用。成功 这些目标的完成将明确宿主对D.汉逊氏菌和微生物逃避 巨噬细胞清除，这将导致识别新的治疗靶点，用于治疗克罗恩病的子集 组织相关性疾病患者D.汉森尼。