Gram-Negative Pneumonia and Lipopolysaccharide Binding Protein

描述（由申请人提供）： 该提案旨在作为创伤外科和外科重症监护学术生涯发展的培训计划。该计划建立在以前的研究经验，并最终导致独立的医学研究的职业生涯。申请人将接触到新的实验技术，将其应用于基础科学研究的新领域，并与两位经验丰富的共同导师互动。该研究项目将重点关注革兰氏阴性细菌肺炎的发病机制，特别是脂多糖结合蛋白（LBP）的作用。LBP是识别LPS的脂质A部分的急性期蛋白。LBP可以由肺组织表达，并且已被证明在革兰氏阴性菌的识别和清除中发挥独特的作用。我们推测LBP是革兰阴性肺炎发病机制中的关键因素。本研究的具体目的包括：1）阐明内源性LBP在革兰阴性菌肺炎发病机制中的作用。2)评估LBP过表达对改变革兰阴性肺炎发病机制的影响。3)通过用LBP样肽抑制LPS的全身识别来阻断革兰氏阴性肺炎的正常发病机制。实验将利用经典的免疫学，分子生物学和基因治疗。此外，研究将集中在蛋白质组学与使用一种新的蛋白质微阵列免疫测定和LBP样肽的发展。长期目标是进一步了解LBP在局部和全身水平对肺部细菌感染的反应。密歇根大学外科系为培养下一代外科医生科学家提供了最佳环境。该计划结合了许多不同顾问的专业知识，概述了研究基础的教学课程，并利用医学院的大量资源提供定制的教学体验。密歇根大学外科学系在培养成功的外科医生-研究者方面有着悠久的历史，共同导师将最大限度地为主要研究者提供机会，成功地为独立研究者长期成功的研究生涯奠定坚实的基础。相关性：细菌性肺炎可导致创伤、烧伤和手术后患者严重发病和死亡。它是美国医院死亡的第六大常见原因，每年的医疗保健费用超过200亿美元。从提出的实验中获得的见解可能会导致新的治疗干预措施，用于治疗和预防细菌性肺炎。

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.