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: 7251966
• 负责人: GILMAN B ALLEN
• 金额: $ 14.3万
• 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/7251966
• 关键词: Acute; Acute Lung Injury; Advisory Committees; Alveolar; Animal Model; Anticoagulant therapy; Attention; Biology; Biomedical Engineering; Boston; Clinical; Collection; Condition; Critical Care; Data; Development; Doctor of Philosophy; Edema; Epithelial; Excision; Fellowship; Fibrin; Fibrinolysis; Fibrinolytic Agents; Foundations; Functional disorder; Funding; Future; Goals; Human; Inflammatory; Injury; Lead; Link; Lung; Lung diseases; Measurement; Mechanical ventilation; Mechanics; Medical Research; Medicine; Mentors; Methods; Morbidity - disease rate; Mus; Neutrophil Infiltration; Pathogenesis; Permeability; Physiological; Play; Prevention; Principal Investigator; Program Development; Proteins; Research; Research Design; Research Personnel; Respiratory System; Respiratory physiology; Risk Factors; Role; Scientist; Seminal; Stress; Syndrome; Techniques; Testing; Thinking; Time; Tissues; Training Programs; Translating; Universities; Ventilator; Ventilator-induced lung injury; Vermont; authority; career; concept; cytokine; insight; interstitial; lung injury; member; mortality; mouse model; pressure; professor; programs; skills; tool; translational study

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）： 该提案描述了一项为期 5 年的医学研究学术职业发展培训计划。 首席研究员吉尔曼·B·艾伦 (Gilman B. Allen) 已在佛蒙特大学完成了为期 3 年的肺科和重症监护医学研究金以及一年的受保护研究时间。 他现在将发展和完善自己作为临床医生科学家的技能，研究纤维蛋白作为急性肺损伤 (ALI) 和呼吸机诱发性肺损伤 (VILI) 中机械肺功能决定因素的作用。 杰森·H.T.贝茨博士将指导首席研究员的科学发展。 贝茨博士是呼吸系统生物工程领域公认的权威，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，并指导过众多研究实习生（博士和医学博士）。 贝茨博士还是佛蒙特州肺病中心 (VLC) 的高级成员，该中心是一个资金充足、多元化的科学家团队，致力于肺病研究。 VLC 的另外两名高级成员和波士顿大学的一名生物医学工程师组成了一个咨询委员会，将在科学和职业发展问题上提供持续的建议。 ALI 小鼠模型的初步数据使我们推测肺泡纤维蛋白积聚对于产生与 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 VILI 随后发生的主要危险因素。 这些概念将在三个具体目标中进行测试。 具体目标 1 将通过证明小鼠肺泡腔内纤维蛋白的积累对于产生与 ALI 相关的肺力学紊乱是必要且充分的，从而建立纤维蛋白与 ALI 之间的关系。 具体目标 2 将寻求建立相反的结果，即在 ALI 情况下通过药物去除肺泡纤维蛋白可改善肺功能。 最后，具体目标 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 发展之间的关联。 通过使用先进的生理测量方法，这项研究有望深入了解重要且常见的临床状况。 该研究计划连同 VLC 内的集体专业知识及其对培养杰出年轻科学家的关注，为实习临床医生科学家提供了理想的环境，以获得发展肺生物学和病理生理学研究生涯所需的多样化和专业技能。