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

描述（由申请人提供）：候选人：贝丝Y。Besecker，医学博士是俄亥俄州州立大学肺部和重症监护部的助理教授。Besecker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博士利用体外和小鼠体内模型进行锌相关吞噬作用研究。她还进行了两项观察性研究，评估锌与重症败血症患者疾病严重程度和死亡率的关系。Besecker博士的短期目标是获得先天免疫/细菌清除特异性免疫生物学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败血症领域的独立翻译研究员。一个长期目标是开发和领导一个翻译，多中心的研究计划，重点是优化营养，以改善危重病人的结果。来自K23辅导职业发展奖的支持将为实现这些目标奠定基础。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-流式细胞术和动物手术; 2）干预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的互动以及参加当地和国际会议来加强培训。环境：Besecker博士的环境有利于优秀的研究。她有五个特殊的R 01资助的研究人员的指导经验，包括导师，拉里施莱辛格博士和共同导师，博士苏珊Koletar的科学支持。Besecker博士从她的研究所，部门，导师那里获得了财政支持，目前是一名 美国国立卫生研究院资助的OSU临床和翻译科学中心KL 2奖。研究：脓毒症是一种对感染的全身性炎症反应，每年造成超过215，000名患者死亡，花费160亿美元。锌具有免疫调节和细胞保护特性，可能是改善脓毒症患者生存的重要疗法。中心假设：在脓毒症受试者中补充锌可改善单核细胞/巨噬细胞（Mo/M）的吞噬作用，从而改善细菌清除，炎症平衡和死亡率。目标1：确定在Zn和ZD脓毒症小鼠中通过补充锌使Mo/M吞噬作用最大化是否可以改善细菌负荷、炎症平衡和死亡率，并确定Fc的贡献？R和CR 3的表达和吞噬功能目的2：确定在严重脓毒症患者中可能影响血浆锌状态、细菌吞噬作用和炎症平衡的范围内补锌的安全性和毒性特征

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