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

基本信息

批准号：
10294382
负责人：
Lauren Disterhoft Palmer
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10294382
关键词：
Academic Medical Centers Acinetobacter baumannii Acinetobacter baumannii pneumonia 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 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 emerging pathogen 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 opportunistic pathogen pathogen pathogenic bacteria prevent randomized controlled study response tenure track therapeutic target ventilator-associated pneumonia

项目摘要

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.

项目概要候选人：到目前为止，我的博士后研究重点是宿主膳食锌对细菌的影响范德堡大学 Eric P. Skaar 博士实验室中鲍曼不动杆菌肺炎的发病机制大学医学中心。我在 Diana Downs 博士的指导下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佐治亚大学肠道沙门氏菌的生物合成。职业目标：我的职业目标是成为顶级研究机构的终身教授该机构与各级学员合作，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 博士和包括 R. Stokes Peebles 博士、C. Henrique Serezani 博士和 Dawn C. Newcomb 博士，他们是该院的金属专家宿主-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生物学。我的指导委员会将继续每两年举行一次会议，并支持我的实践、说教和职业发展培训帮助我过渡到独立。研究策略：世界卫生组织估计，16% 的人因缺锌而死亡。全球范围内降低呼吸道感染。我们令人兴奋的初步数据表明，锌缺乏显着感染后 24 小时，鲍曼不动杆菌肺炎的死亡率增加，并且 2 型鲍曼不动杆菌肺炎的中和作用细胞因子 IL-13 可以保护小鼠免于死亡。该提案的中心假设是膳食锌缺乏症会在肺部感染期间促进 2 型炎症，从而阻止鲍曼不动杆菌被杀灭。意义和创新：该研究计划将确定该联系背后的分子机制缺锌与肺炎之间。拟议的实验将发现潜在的治疗靶点促进肺部先天免疫。目标 1 (K99)：确定锌缺乏对白细胞介导的细菌杀灭的影响。我们将使用复杂的动物模型测试缺锌对离体和体内白细胞功能的影响以及一套经过改造的荧光鲍曼不动杆菌，用于对宿主-病原体界面进行实时成像。目标 2 (R00)：确定缺锌促进 2 型免疫反应的机制肺部细菌感染。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气道上皮研究缺锌对人气道上皮细胞初始炎症的影响对感染的反应可驱动肺粘膜免疫。过渡到独立：这些目标是独立于斯卡尔博士和我的合作导师制定的，他们不会追求重叠的研究计划。 K99期间，我将申请全国的教职职位。