The impact of dietary zinc deficiency on innate immunity to lung infection

膳食缺锌对肺部感染先天免疫力的影响

• 批准号: 10005451
• 负责人: Lauren Disterhoft Palmer
• 金额: $ 12.44万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005451
• 关键词: Academic Medical Centers; Acinetobacter baumannii; Affect; Anabolism; Animal Model; Animals; Anthelmintics; Antibacterial Response; Bacteria; Biological; Biology; Cell Maintenance; Cessation of life; Child; Cytokine Signaling; Data; Defect; Diet; Dietary Zinc; Doctor of Philosophy; Engineering; Ensure; Environmental Risk Factor; Epithelial; Epithelial Cells; Epithelium; Faculty; Flow Cytometry; Genetic Engineering; Germ Cells; Goals; HIV; Health; Human; Image; Immune; Immune System Diseases; Immunity; Immunology; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Institution; Interleukin-13; Invaded; Laboratories; Leukocytes; Life; Link; Lower Respiratory Tract Infection; Lung; Lung infections; Lymphopoiesis; Measures; Mediating; Mentors; Metabolism; Metals; Microbiology; Modeling; Molecular; Mucosal Immunity; Multi-Drug Resistance; Mus; Natural Immunity; Nutrient; Observational Study; Opportunistic Infections; Outcome; Pathogenesis; Pathogenicity; Patients; Persons; Phagocytosis; Phase; Phenotype; Pneumonia; Population; Positioning Attribute; Predisposition; Production; Regulation; Research; Resolution; Risk; Role; Salmonella enterica; Signal Transduction; Source; Structure of respiratory epithelium; Testing; Thiamine; Time; Training; Training Activity; Universities; Wisconsin; Work; World Health Organization; Zinc; Zinc deficiency; Zinc supplementation; airway epithelium; bacterial genetics; bronchial epithelium; career; career development; cell type; cytokine; experimental study; high risk; human pathogen; immune function; in vivo; innate immune function; innate immune mechanisms; innovation; insight; macrophage; member; mortality; mouse model; multi-drug resistant pathogen; neutrophil; novel; nutrition; pathogen; pathogenic bacteria; prevent; randomized controlled study; response; tenure track; therapeutic target; ventilator-associated pneumonia

PROJECT SUMMARY Candidate: My postdoctoral research thus far focused on the effects of host dietary zinc on bacterial pathogenesis during Acinetobacter baumannii pneumonia in Dr. Eric P. Skaar's laboratory at Vanderbilt University Medical Center. I earned my PhD in Microbiology with Dr. Diana Downs studying thiamine (vitamin B1) biosynthesis in Salmonella enterica at the University of Wisconsin-Madison and the University of Georgia. Career Goals and Objectives: My career goal is to be a tenure-track faculty member at a top-tier research institution working with trainees at all levels to understand how metabolism affects the host-pathogen interface. In order to achieve this goal, I need additional mentored training in host inflammation and immunology. Career Development and Training Activities: My mentoring committee will be led by Dr. Skaar and include Dr. R. Stokes Peebles, Dr. C. Henrique Serezani, and Dr. Dawn C. Newcomb, experts in metals at the host-pathogen interface, infection imaging, type 2 lung immunity, innate inflammation, and respiratory epithelial biology. My mentoring committee will continue to meet biannually and support my practical, didactic, and career development training to aid my transition to independence. Research Strategy: The World Health Organization estimated that zinc deficiency contributes to 16% of lower respiratory infections globally. Our exciting preliminary data show that zinc deficiency significantly increases mortality from A. baumannii pneumonia by 24 h post infection, and that neutralization of the type 2 cytokine IL-13 protects mice from mortality. The central hypothesis of this proposal is that dietary Zn deficiency promotes type 2 inflammation during lung infection, preventing A. baumannii killing. Significance and Innovation: The research plan will identify molecular mechanisms underlying the link between zinc deficiency and pneumonia. The proposed experiments will uncover potential therapeutic targets to promote lung innate immunity. Aim 1 (K99): Determine the effect of Zn deficiency on leukocyte-mediated bacterial killing. We will test the effect of zinc deficiency on leukocyte function ex vivo and in vivo using sophisticated animal models and an engineered suite of fluorescent A. baumannii to image the host-pathogen interface in real time. Aim 2 (R00): Identify the mechanism by which Zn deficiency promotes type 2 immunity in response to bacterial lung infection. We will identify the cellular source of IL-13 and upstream cytokine signaling by the airway epithelium to investigate the effect of Zn deficiency on human airway epithelial cell initial inflammatory response to infection that drives lung mucosal immunity. Transition to independence: These aims were developed independently of Dr. Skaar and my co-mentors, and they will not pursue overlapping research plans. During the K99, I will apply for faculty positions nationally.

项目摘要 候选人：到目前为止，我的博士后研究主要集中在宿主膳食锌对细菌的影响。 范德比尔特Eric P. Skaar博士实验室鲍曼不动杆菌肺炎期间的发病机制 大学医学中心。我在Diana唐斯博士那里获得了微生物学博士学位，研究硫胺素（维生素 B1）威斯康星大学麦迪逊分校和格鲁吉亚大学的肠道沙门氏菌生物合成。 职业目标：我的职业目标是成为一名顶级研究机构的终身教职员工。 该机构与各级受训人员合作，了解新陈代谢如何影响宿主-病原体界面。 为了实现这一目标，我需要在宿主炎症和免疫学方面进行额外的指导培训。 职业发展和培训活动：我的指导委员会将由Skaar博士领导， 包括R博士。斯托克斯皮布尔斯，C医生。Henrique Serezani和Dawn C.纽科姆，在金属专家在 宿主-病原体界面、感染成像、2型肺免疫、先天性炎症和呼吸道上皮细胞 生物学我的指导委员会将继续每半年举行一次会议，并支持我的实践，教学， 职业发展培训，以帮助我过渡到独立。 研究策略：世界卫生组织估计，缺锌导致16%的 下呼吸道感染全球。我们令人兴奋的初步数据表明，缺锌显着 增加了A.在感染后24小时，鲍曼不动杆菌肺炎和2型中和 细胞因子IL-13保护小鼠免于死亡。该建议的核心假设是，膳食锌 在肺部感染期间，缺乏促进2型炎症，防止A.鲍曼不动杆菌。 意义和创新：研究计划将确定这种联系的分子机制 锌缺乏和肺炎之间的联系拟议的实验将揭示潜在的治疗靶点 促进肺部先天免疫。 目的1（K99）：确定锌缺乏对白细胞介导的细菌杀伤的影响。我们将 使用复杂的动物模型测试锌缺乏对离体和体内白细胞功能的影响 和一套荧光A鲍曼不动杆菌来对宿主-病原体界面进行真实的成像。 目的2（R 00）：确定锌缺乏促进2型免疫反应的机制 细菌性肺部感染我们将通过以下方法鉴定IL-13和上游细胞因子信号传导的细胞来源： 探讨锌缺乏对人气道上皮细胞初始炎症反应的影响 对感染的反应，驱动肺粘膜免疫。 过渡到独立：这些目标是独立于Skaar博士和我的合作导师开发的， 也不会进行重叠的研究计划。在K99期间，我将申请全国教师职位。