Interactions of Intestinal Epithelial Cells, The Innate Immune System and Gut Microbiota During Dysbiosis

菌群失调期间肠上皮细胞、先天免疫系统和肠道微生物群的相互作用

• 批准号: 10223287
• 负责人: Charles Preston Neff
• 金额: $ 14.83万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223287
• 关键词: Address; Automobile Driving; Award; Bacteria; Bioinformatics; Biometry; Cell Communication; Cell Line; Cells; Chronic; Clinical Immunology; Collaborations; Colorado; Communities; Cytometry; Dendritic Cells; Digestive System Disorders; Disease; Environment; Epithelial; Epithelial Cells; Feces; Gastrointestinal Diseases; Goals; Grant; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; Human; Hypersensitivity; Immune; Immunology; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune System; Intestines; Lamina Propria; Lead; Ligands; Light; Lipopolysaccharides; Liquid Chromatography; Lung; Mass Spectrum Analysis; Medical; Mentors; Mentorship; Methods; Modeling; Monitor; Mononuclear; Mucous Membrane; Peptidoglycan; Performance; Peripheral; Peripheral Blood Mononuclear Cell; Phenols; Property; Publishing; Regulatory T-Lymphocyte; Research; Research Project Grants; Sex Behavior; Stimulus; Structure; TLR2 gene; TLR4 gene; Taxonomy; Testing; Training; Translational Research; Universities; Variant; Virus Diseases; Water; Work; Writing; bacterial community; base; career development; dysbiosis; enteric dysbiosis; experimental study; fecal microbiome; gut microbiome; gut microbiota; host microbiome; host microbiota; humanized mouse; immune activation; immunoregulation; instructor; intestinal epithelium; liquid chromatography mass spectrometry; macrophage; men who have sex with men; microbial; microbiome; microbiota; novel; novel therapeutics; post-doctoral training; programs; responsible research conduct; time use; treatment strategy

PROJECT SUMMARY/ABSTRACT Candidate: The applicant is an instructor in the Allergy and Clinical Immunology Division at the University of Colorado Anschutz Medical Campus. The applicant’s thesis work under the mentorship of Dr. Ramesh Akkina at Colorado State University focused on translational research utilizing humanized mice to develop novel therapies against HIV infection. During his Post-doctoral training, Dr. Neff developed methods to characterize the impact of the fecal microbiome on adaptive immune cells, found regulatory T cell inducing products in bacteria and characterized the impact of HIV infection on immune cells in the lung. Environment: At the University of Colorado, the applicant has a mentoring team with immunology, mucosal immunology, inflammation and microbiome expertise in primary mentor Dr. Brent Palmer, and co-mentors Drs. Catherine Lozupone, Sean Colgan, and Laurel Lenz. The applicant will continue close collaboration with Drs. Nichole Reisdorph and Timothy Bushnell who will serve as technical advisors for UPLC, mass spectrometry and CyTOF. The applicant’s training plan during the award includes bioinformatics, immunology, biostatistics, responsible conduct of research, and programs in grant writing and career development. Research: Chronic immune activation is a hallmark of HIV infection and recently, changes in the composition of the enteric microbiome have been implicated as a driving factor. However, the mechanisms of host:microbiome interactions are poorly understood. We showed that the fecal microbiome from those with HIV has inflammatory properties not seen in taxonomically similar healthy subjects. Using this HIV-associated microbiome as a model present a unique opportunity to identify causal bacteria and the mechanisms in which they lead to cell activation. The applicant’s long-term goal is to develop a deeper understanding of the bacterial products that drive chronic immune activation as a means to advance treatment strategies for inflammatory gastrointestinal diseases. This proposal will evaluate the mechanisms of microbiota:host interactions. Based on previous findings, which indicated peptidoglycan (PGN) and lipopolysaccharide (LPS) as drivers of inflammatory responses, this proposal will also investigate if specific variants of PGN and LPS differentially induce aberrant activation. The central hypothesis is that specific PGN and LPS forms found with bacteria increased during HIV convey differential inflammatory properties. The first aim will characterize the interactions of epithelial cells, subsets of innate immune cells and the microbiome during HIV dysbiosis in order to determine rare bacteria that cause inflammation. The second aim will focus on purifying PGN and LPS to determine if strain specific forms of these bacterial products are responsible for inducing aberrant cell activation. The findings here could have global implications of the treatment of chronic immune activation seen in multiple diseases.

项目总结/摘要 候选人：申请人是过敏和临床免疫学系的讲师， 科罗拉多安舒茨医学院。在Ramesh Akkina博士的指导下，申请人的论文工作 在科罗拉多州立大学的一项研究中， 针对艾滋病毒感染的疗法。在博士后培训期间，Neff博士开发了描述 粪便微生物组对适应性免疫细胞的影响，在细菌中发现调节性T细胞诱导产物 并描述了艾滋病毒感染对肺部免疫细胞的影响。 环境：在科罗拉多大学，申请人有一个免疫学、粘膜学和免疫学指导团队。 免疫学、炎症和微生物组学专业知识的主要导师布伦特帕尔默博士和共同导师 凯瑟琳·洛祖彭，肖恩·科尔根，还有月桂伦茨。申请人将继续与博士密切合作。 Nichole Reisdorph和Timothy Bushnell将担任UPLC、质谱和 CyTOF。申请人在获奖期间的培训计划包括生物信息学，免疫学，生物统计学， 负责任地进行研究，并在赠款写作和职业发展计划。 研究：慢性免疫激活是艾滋病毒感染的标志，最近， 肠道微生物组被认为是一个驱动因素。然而，宿主的机制：微生物组 相互作用知之甚少。我们发现，HIV感染者的粪便微生物组具有炎症性 在分类学上相似的健康受试者中看不到的特性。利用这种与艾滋病病毒相关的微生物组作为模型， 提供了一个独特的机会，以确定致病细菌和它们导致细胞活化的机制。 申请人的长期目标是更深入地了解驱动慢性炎症的细菌产物。 免疫激活作为推进炎症性胃肠疾病治疗策略的手段。这 该提案将评估微生物群的机制：宿主相互作用。根据以前的研究结果， 表明肽聚糖（PGN）和脂多糖（LPS）是炎症反应的驱动因素， 还将研究PGN和LPS的特定变体是否差异诱导异常激活。中央 假设在HIV传播差异期间，细菌中发现特异性PGN和LPS形式增加 炎症特性。第一个目标将表征上皮细胞，先天性免疫缺陷的亚群， 免疫细胞和微生物组在HIV生态失调，以确定罕见的细菌， 炎症第二个目标将集中于纯化PGN和LPS，以确定是否存在这些的菌株特异性形式。 细菌产物是诱导异常细胞活化的原因。这里的发现可能具有全球性 在多种疾病中观察到的慢性免疫激活治疗的影响。