Gram-Negative Pneumonia and Lipopolysaccharide Binding Protein

革兰氏阴性肺炎和脂多糖结合蛋白

• 批准号: 7136692
• 负责人: MARK RICHARD HEMMILA
• 金额: $ 12.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7136692
• 关键词: Adenoviridae; CD14 molecule; antiinfective agents; bacterial cytopathogenic effect; binding proteins; cytokine; cytoprotection; gene induction /repression; gram negative bacteria; inflammation; intermolecular interaction; leukocyte activation /transformation; lipopolysaccharides; microarray technology; neutrophil; pathologic process; patient oriented research; peptide chemical synthesis; pneumonia; protein localization; toll like receptor; transfection /expression vector

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.

描述（由申请人提供）： 该建议被设计为开发创伤手术和手术重症监护职业生涯的培训计划。该计划以先前的研究经验为基础，并最终导致独立医学研究的职业。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，并与两个经验丰富的院长互动。该研究项目将集中于革兰氏阴性细菌性肺炎的发病机理，特别是关于脂多糖结合蛋白（LBP）的作用。 LBP是一种急性相蛋白，可以识别LPS的脂质部分。 LBP可以通过肺组织表达，并且已显示在革兰氏阴性细菌的识别和清除率中起着独特的作用。我们假设LBP是革兰氏阴性肺炎发病机理中的关键要素。拟议研究的具体目的包括：1）阐明内源性LBP在革兰氏阴性细菌肺炎发病机理中的作用。 2）评估LBP过表达对改变革兰氏阴性肺炎发病机理的影响。 3）通过抑制具有LBP（如肽）的LBS的全身识别，阻止革兰氏阴性肺炎的正常发病机理。提出的实验将利用经典的免疫学，分子生物学和基因治疗。此外，该研究将通过使用新型蛋白微阵列免疫测定和LBP样肽的发育来关注蛋白质组学。长期目标是进一步了解LBP在局部和系统水平上对肺部细菌感染反应的作用。密歇根大学外科系为培训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，研究基础上的教学课程概述，并利用医学院的庞大资源来提供定制的教学经验。密歇根大学外科系有悠久的历史，培育了成功的外科医生评估者，而委托人将最大限度地机会，首席研究人员成功地为作为独立研究员的漫长而成功的研究职业建立了合理的基础。相关性：细菌性肺炎会导致创伤，烧伤和手术后患者的严重发病率和死亡率。这是美国在美国死亡的第六大医院死亡原因，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，以预防细菌性肺炎。