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

项目总结 候选人：到目前为止，我的博士后研究主要集中在宿主饮食锌对细菌的影响 范德比尔特埃里克·P·斯卡博士实验室鲍曼不动杆菌肺炎的发病机制 大学医学中心。我获得了微生物学博士学位，师从戴安娜·唐斯博士，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的肠炎沙门氏菌的生物合成。 职业目标和目的：我的职业目标是成为一名顶尖研究机构的终身教员 该机构与所有级别的受训人员合作，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博士和 包括R.Stokes Peeble博士，C.Henrique Serezani博士和Dawn C.Newcomb博士， 宿主-病原体界面、感染成像、2型肺免疫、先天炎症和呼吸道上皮细胞 生物学。我的指导委员会将继续每两年召开一次会议，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 全球范围内的下呼吸道感染。我们令人振奋的初步数据显示，缺锌显著 增加感染后24小时鲍曼不动杆菌肺炎的死亡率，并中和2型 细胞因子IL-13保护小鼠免于死亡。这一建议的中心假设是饮食中的锌 缺乏促进肺部感染期间的2型炎症，防止鲍曼不动杆菌死亡。 意义和创新：该研究计划将确定这种联系背后的分子机制 缺锌和肺炎之间的关系。拟议中的实验将发现潜在的治疗靶点。 促进肺的先天免疫。 目的1(K99)：确定缺锌对白细胞介导的细菌杀灭的影响。我们会 用复杂动物模型检测缺锌对体内外白细胞功能的影响 以及一套经过设计的荧光鲍曼不动杆菌，以实时成像宿主与病原体的界面。 目的2(R00)：确定缺锌促进2型免疫应答的机制 导致细菌性肺部感染。我们将通过以下途径确定IL-13和上游细胞因子信号的细胞来源 呼吸道上皮细胞缺锌对人气道上皮细胞初始炎症的影响 对感染的反应，推动肺粘膜免疫。 过渡到独立：这些目标是在斯卡博士和我的共同导师的帮助下独立制定的， 他们不会追求重叠的研究计划。在K99考试期间，我将在全国范围内申请教职。

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.