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.
| Tetenev, Konstantin; Cloutier, Mary E; von Reyn, Jessica A et al. (2015) Synergy between acid and endotoxin in an experimental model of aspiration-related lung injury progression. Am J Physiol Lung Cell Mol Physiol 309:L1103-11 |
| Allen, Gilman B; Cloutier, Mary E; Larrabee, Yuna C et al. (2009) Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 296:L277-85 |
| Allen, Gilman B; Leclair, Timothy R; von Reyn, Jessica et al. (2009) Acid aspiration-induced airways hyperresponsiveness in mice. J Appl Physiol 107:1763-70 |
| Allen, Gilman B; Leclair, Timothy; Cloutier, Mary et al. (2007) The response to recruitment worsens with progression of lung injury and fibrin accumulation in a mouse model of acid aspiration. Am J Physiol Lung Cell Mol Physiol 292:L1580-9 |
| Allen, Gilman B; Suratt, Benjamin T; Rinaldi, Lisa et al. (2006) Choosing the frequency of deep inflation in mice: balancing recruitment against ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 291:L710-7 |
