Critical Role of Alveolar Fibrin in Acute Lung Injury

肺泡纤维蛋白在急性肺损伤中的关键作用

• 批准号: 6918651
• 负责人: GILMAN B ALLEN
• 金额: $ 14.1万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918651
• 关键词: acute disease /disorder; biomarker; biomechanics; disease /disorder model; disease /disorder proneness /risk; enzyme linked immunosorbent assay; fibrin; fibrinolysis; fibrinolytic agents; fibrinolytic therapy; genetically modified animals; laboratory mouse; lung alveolus; lung injury; mechanical stress; protein metabolism; respirators; respiratory function; video microscopy

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in medical research. The principal investigator, Gilman B. Allen, has completed a 3-year fellowship in pulmonary and critical care medicine and an additional year of protected research time at the University of Vermont. He will now develop and refine his skills as a clinician-scientist investigating the role of fibrin as a determinant of mechanical lung function in acute lung injury (ALI) and ventilator-induced lung injury (VILI). Jason H.T. Bates, PhD, will mentor the principal investigator's scientific development. Dr. Bates is a recognized authority on the bioengineering aspects of the respiratory system and has made seminal contributions to our understanding of pulmonary mechanics. Dr. Bates is a Research Professor in the Department of Medicine, and has mentored numerous research trainees (both PhD and MD). Dr. Bates is also a senior member of the Vermont Lung Center (VLC), a well-funded and diverse collection of scientists collaborating on research in pulmonary disease. Two other senior members of the VLC and a biomedical engineer from Boston University constitute an advisory committee that will provide ongoing advice in both scientific and career development matters. Preliminary data from mouse models of ALI lead us to hypothesize that alveolar fibrin accumulation is critical for producing the changes in lung mechanics associated with ALI. We also suspect that alveolar fibrin is a major risk factor for the subsequent development of VILI. These concepts will be tested in three specific aims. Specific Aim 1 will establish the relationship between fibrin and ALI by showing that accumulation of fibrin within the alveolar space of mice is both necessary and sufficient to produce the derangements of lung mechanics associated with ALI. Specific Aim 2 will then seek to establish the converse, that the pharmacologic removal of alveolar fibrin in the setting of ALI leads to an improvement in lung function. Finally, Specific Aim 3 will explore the association between alveolar fibrin levels and development of VILI through the application of injurious modes of mechanical ventilation in mouse models of ALI. By using advanced methods of physiological measurement, this research is expected to provide insight into an important and common clinical condition. This program of research, together with the collective expertise within the VLC and its focus on nurturing exceptional young scientists, constitute an ideal setting for a trainee clinician-scientist to attain the diverse and specialized skills necessary to develop a research career in lung biology and pathophysiology.

描述（由申请人提供）： 该建议描述了一项为期5年的医学研究学术生涯的培训计划。 首席研究员吉尔曼·艾伦（Gilman B. 现在，他将发展并完善自己作为临床医生的技能，研究纤维蛋白作为机械肺功能在急性肺损伤（ALI）和呼吸机诱导的肺损伤（VILI）中的作用。 Jason H.T.贝茨（Bates）博士将指导主要研究者的科学发展。 贝茨博士是呼吸系统生物工程方面的公认权威，并为我们对肺力学的理解做出了开创性的贡献。 贝茨博士是医学系的研究教授，并指导了许多研究学员（博士学位和医学博士）。 贝茨博士还是佛蒙特州肺中心（VLC）的高级成员，这是一家资金丰富且多样化的科学家，在肺部疾病研究方面合作。 VLC的另外两名高级成员和波士顿大学的生物医学工程师组成了一个咨询委员会，该委员会将在科学和职业发展事务方面提供持续的建议。 来自ALI小鼠模型的初步数据使我们假设肺泡纤维蛋白的积累对于产生与ALI相关的肺力学变化至关重要。 我们还怀疑肺泡纤维蛋白是随后发展VILI的主要危险因素。 这些概念将以三个特定目标进行测试。 特定的目标1将通过表明纤维蛋白和ALI之间的关系来证明纤维蛋白在小鼠的肺泡空间内的积累既需要且足以产生与Ali相关的肺力学的危险。 然后，特定的目标2将寻求建立相反的问题，即在ALI的情况下，肺泡纤维蛋白的药理去除会导致肺功能的改善。 最后，特定的目标3将通过在ALI小鼠模型中应用机械通气的有害模式来探索肺泡纤维蛋白水平与VILI的发展之间的关联。 通过使用先进的生理测量方法，这项研究有望提供对重要且常见的临床状况的见解。 这项研究计划以及VLC中的集体专业知识及其关注培养卓越的年轻科学家的关注，构成了学员临床医生 - 科学家的理想环境，以获得发展肺部生物学和病理生理学研究生涯所必需的多样化和专业技能。