The Impact of Zinc on Innate Immunity and Patient Safety in Sepsis

应聘者：Beth Y.Besecker，医学博士，俄亥俄州立大学肺与重症监护科助理教授。贝塞克博士最初的基础科学研究评估了锌在肺上皮细胞中的细胞保护作用。最近，她参与了一项翻译研究，评估锌在细菌吞噬和清除脓毒症中的作用。Besecker博士使用了体外和小鼠体内模型来研究锌相关的吞噬作用。她还进行了两项观察性研究，评估锌与重症脓毒症患者病情严重程度和死亡率的关系。Besecker博士的短期目标是获得特定于先天免疫/细菌清除的免疫生物学方面的培训，以及临床研究设计和实施方面的培训，使她能够过渡到锌免疫生物学和脓毒症领域的独立翻译研究员。更长期的目标是开发和领导一个转化性的、多中心的研究计划，专注于优化营养以改善危重患者的预后。来自K23指导职业发展奖的支持将为实现这些目标提供基础。职业发展：Besecker博士的职业发展/培训将涵盖4个核心领域，包括：1)实验室技术--流式细胞术和动物外科；2)介入性临床试验的设计和管理；3)项目管理/研究计划的组织；4)核心知识--免疫生物学、药理学和生物统计学。还将通过与指导小组成员互动以及参加当地和国际会议来加强培训。环境：贝塞克博士所处的环境有利于优秀的研究。她得到了五位特别的R01资助的具有指导经验的研究人员的科学支持，其中包括导师拉里·施莱辛格博士和共同导师苏珊·科莱塔博士。Besecker博士得到了她的研究所、部门、导师的财政支持，目前是一名 国立卫生研究院资助的俄亥俄州立大学临床和翻译科学中心KL2奖。研究：败血症是对感染的一种全身炎症反应，每年导致超过21.5万名患者死亡，造成160亿美元的损失。锌具有免疫调节和细胞保护特性，可能是提高脓毒症患者存活率的重要疗法。中心假设：脓毒症患者补锌可改善单核/巨噬细胞(Mo/M�)吞噬功能，从而改善细菌清除、炎症平衡和死亡率。目的1：确定补锌是否能最大限度地提高锌和锌脓毒症小鼠的Mo/M�吞噬功能，改善细菌负荷、炎症平衡和死亡率，并确定Fc？R和CR3的表达和功能对吞噬功能的贡献。目标2：在可能影响严重脓毒症患者血浆锌状态、细菌吞噬和炎症平衡的范围内，确定补锌的安全性和毒性

DESCRIPTION (provided by applicant): Candidate: Beth Y. Besecker, M.D. is an Assistant Professor in the Pulmonary and Critical Care Division at The Ohio State University. Dr. Besecker's initial basic science research evaluated zinc's cytoprotective role in lung epithelia. Recently she has been involved in translational research evaluating the role of zinc in bacterial phagocytosis and clearance in sepsis. Dr. Besecker utilizes both an in vitro and murine in vivo model for her zinc-related phagocytosis studies. She has also conducted two observational studies evaluating zinc's relation to the severity of illness and mortality in critically ill septi patients. Dr. Besecker's short term goal is to obtain training in both immunobiology specific to innate immunity/ bacterial clearance and clinical research design and implementation to allow her to transition to an independent translational researcher in the areas of zinc immunobiology and sepsis. A longer term goal is to develop and lead a translational, multi-center research program that focuses on optimizing nutrition to improve patient outcomes in the critically ill. Support from a K23 Mentored Career Development Award would provide the foundation to attain these goals. Career Development: Dr. Besecker's career development/ training will cover 4 Core Areas and include: 1) Laboratory techniques- flow cytometry and animal surgery; 2) Design and management of interventional clinical trials; 3) Project Management/ Organization of Research Programs; 4) Core Knowledge- immunobiology, pharmacology, and biostatistics. Training will also be enhanced by interaction with mentor team members and participation in local and international meetings. Environment: Dr. Besecker's environment is conducive to excellent research. She has the scientific support of five exceptional R01 funded investigators with mentoring experience including Mentor, Dr. Larry Schlesinger and Co-mentor, Dr. Susan Koletar. Dr. Besecker has financial support from her institute, division, mentors, and currently an NIH-funded OSU Center for Clinical and Translation Sciences KL2 award. Research: Sepsis, a systemic inflammatory response to infection, kills over 215,000 patients and costs 16 billion dollars annually. Zinc has immune regulatory and cell protective properties and may be an important therapy for improved survival in patients with sepsis. Central Hypothesis: Zinc supplementation in septic subjects improves monocyte/macrophage (Mo/M�) phagocytosis and consequently improves bacterial clearance, inflammatory balance, and mortality. Aim 1: Determine whether maximization of Mo/M� phagocytosis by zinc supplementation in Zn and ZD septic mice can improve bacterial burden, inflammatory balance, and mortality and determine the contribution of Fc?R and CR3 expression and function to phagocytosis Aim 2: Determine the safety and toxicity profile of zinc supplementation over a range that may impact plasma zinc status, bacterial phagocytosis, and inflammatory balance in patients with severe sepsis