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

项目摘要/摘要 应聘者：申请人是加州大学过敏和临床免疫学系的讲师。 科罗拉多州安舒茨医学院。申请人的论文是在Ramesh Akina博士的指导下完成的 在科罗拉多州立大学，专注于利用人源化小鼠进行翻译研究，以开发新的 针对艾滋病毒感染的治疗方法。在他的博士后培训期间，内夫博士开发了一些方法来描述 粪便微生物对适应免疫细胞的影响，在细菌中发现了调节性T细胞诱导产物 并表征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，申请者有一个免疫学、粘膜学指导团队 主要导师布伦特·帕尔默博士和共同导师布伦特·帕尔默博士的免疫学、炎症和微生物组专业知识。 凯瑟琳·洛祖彭、肖恩·科尔根和劳蕾尔·伦茨。申请者将继续与博士密切合作。 尼科尔·赖斯多夫和蒂莫西·布什内尔将担任UPLC、质谱学和 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，制定拨款和职业发展计划。 研究：慢性免疫激活是HIV感染的标志，最近，病毒成分的变化 肠道微生物群被认为是一个驱动因素。然而，寄主的机制：微生物群 人们对相互作用知之甚少。我们发现HIV感染者的粪便微生物群具有炎症性。 在分类学上相似的健康受试者中未见的特性。用这种与HIV相关的微生物群作为模型 提供了一个独特的机会来识别致病细菌和它们导致细胞激活的机制。 申请者的长期目标是加深对导致慢性疾病的细菌产品的了解 免疫激活作为推进炎症性胃肠道疾病治疗策略的一种手段。这 提案将评估微生物区系的机制：宿主相互作用。根据之前的调查结果， 指出肽聚糖(PGN)和脂多糖(LPS)是炎症反应的驱动因素，这项提议 还将研究PGN和内毒素的特定变体是否会以不同的方式诱导异常激活。中环 假说是在HIV病毒传播过程中发现的特定PGN和内毒素形式随着细菌的增加而增加 炎性物质。第一个目标将描述上皮细胞、先天亚群之间的相互作用 免疫细胞和微生物组在HIV生物失调过程中的作用，以确定引起 发炎。第二个目标将集中在纯化PGN和内毒素，以确定这些菌株的特定形式 细菌产物是导致细胞异常激活的原因。这里的发现可能会在全球范围内 慢性免疫激活治疗在多种疾病中的意义。

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 im pact of the fecal m icrobiom e on adaptive im m une 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 lipopollysaccharide (LPS) as drivers of infammatory responses, this proposal will also investigate if specific variants of PGN and LPS differentally 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.