Gram-Negative Pneumonia and Lipopolysaccharide Binding Protein

描述(由申请人提供)： 这项提案旨在为创伤外科和外科危重护理领域的学术生涯发展提供培训计划。该计划建立在以前的研究经验的基础上，最终导致了独立医学研究的职业生涯。申请者将接触到新的实验技术，将它们应用于基础科学研究的新领域，并与两名经验丰富的合作导师互动。该研究项目将集中在革兰氏阴性细菌性肺炎的发病机制上，特别是关于脂多糖结合蛋白(LBP)的作用。LBP是一种急性时相蛋白，能识别脂多糖的脂类A部分。LBP可以在肺组织中表达，在革兰氏阴性菌的识别和清除中发挥着独特的作用。我们推测LBP在革兰氏阴性肺炎的发病机制中是一个关键因素。本研究的具体目的包括：1)阐明内源性LBP在革兰氏阴性细菌性肺炎发病机制中的作用。2)探讨LBP过度表达在革兰氏阴性肺炎发病机制中的作用。3)通过抑制LBP样肽对内毒素的系统识别，阻断革兰氏阴性肺炎的正常发病机制。提议的实验将利用经典的免疫学、分子生物学和基因疗法。此外，研究将集中在蛋白质组学，使用一种新的蛋白质微阵列免疫分析和开发LBP样多肽。长期目标是加深我们对LBP在局部和全身水平上应对肺部细菌感染的作用的理解。密歇根大学的外科系为培养下一代外科科学家提供了最佳的环境。这一计划结合了许多不同顾问的专业知识，概述了研究基础方面的教学课程，并利用医学院的大量资源提供定制的教学经验。密歇根大学外科在培养成功的外科调查人员方面有着悠久的历史，联合导师将最大限度地增加首席调查人员成功为作为独立调查人员的长期和成功的研究生涯奠定坚实基础的机会。相关性：细菌性肺炎可导致创伤、烧伤和手术后患者的严重发病率和死亡率。它是美国医院死亡的第六大常见原因，每年导致的医疗费用超过200亿美元。从拟议的实验中获得的见解可能会导致治疗和预防细菌性肺炎的新的治疗干预措施。

DESCRIPTION (provided by applicant): This proposal is designed as a training program for the development of an academic career in Trauma Surgery and Surgical Critical Care. The program builds on prior research experiences and ultimately leads to a career of independent medical research. The applicant will be exposed to new experimental techniques, apply them to a new area of basic science research, and interact with two experienced co-mentors. The research project will focus on the pathogenesis of Gram-negative bacterial pneumonia, specifically with respect to the role of lipopolysaccharide binding protein (LBP). LBP is an acute phase protein that recognizes the lipid A moiety of LPS. LBP can be expressed by lung tissue and has been shown to play a unique role in the recognition and clearance of Gram-negative bacteria. We hypothesize that LBP is a key element in the pathogenesis of Gram-negative pneumonia. The specific aims of the proposed research include: 1) Elucidating the role of endogenous LBP in the pathogenesis of Gram-negative bacterial pneumonia. 2) Evaluate the effect of over-expression of LBP on altering the pathogenesis of Gram-negative pneumonia. 3) Block the normal pathogenesis of Gram-negative pneumonia by inhibiting the systemic recognition of LPS with LBP like peptides. The experiments proposed will utilize classic immunology, molecular biology, and gene therapy. In addition the research will focus on proteomics with use of a novel protein microarray immunoassay and development of LBP-like peptides. The long-term goal is to further our understanding of the role of LBP at the local and systemic level in responding to bacterial infection within the lung. The Surgery Department of the University of Michigan provides an optimal setting for training the next generation of surgeon-scientists. This program incorporates the expertise of many different advisors, outlines didactic coursework in research fundamentals, and draws on the vast resources of the Medical School to provide a customized teaching experience. The University of Michigan Department of Surgery has a long history of nurturing successful surgeon-investigators and the co-mentors will maximize the opportunity for the principal investigator to succeed in establishing a sound foundation for a long and successful research career as an independent investigator. Relevance: Bacterial pneumonia can lead to severe morbidity and mortality in trauma, burn and post- surgical patients. It is the sixth most common cause of hospital death within the United States and results in health care costs of greater than $20 billion per year. The insights gained from the experiments proposed may lead to new therapeutic interventions for treatment and prevention of bacterial pneumonia.