Role of Growth Arrest and DNA Damage 45-alpha in Acute Lung Injury Pathogenesis

University Of Chicago, Chicago IL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Acute Lung Injury (All) is a common and devastating disorder, afflicting an estimated 190,000 patients each year in the United States and inflicting a mortality rate of 30 - 50%. Treatment of ALI invariably necessitates mechanical ventilation, which can itself potentiate or even induce lung injury. To date, our only proven therapies for ALI are to employ a non-injurious ventilation strategy and to limit excess intravenous fluid administration. As only a minority of the patients with risk factors for the disease will develop the full-blown syndrome of airspace flooding and profound hypoxemia, a better understanding of ALI susceptibility might lead to improved and more personalized therapy. Our studies focused on expression profiling of animal and human ALI to explore potential genetic contributions to the development of ALI revealed significantly elevated expression of a number of genes potentially implicated in the pathogenesis of ALI. Growth arrest and DNA damage-inducible gene 45 alpha (GADD45a), a constitutively expressed gene activated by cellular injuries resulting in DNA damage or cell cycle arrest, is one such gene with intense upregulation in response to ALI. While it has no known action in the lung to date, we hypothesize that GADD45a is a viable candidate gene which confers protection against ALI. In this application, the principal investigator will study mechanisms by which GADD45a may influence acute lung injury. Specific Aim #1 will employ an animal model of both ventilator-induced and sepsis- induced ALI to test whether a GADD45a knockout strain is more susceptible to lung injury. We will characterize the spatial location of GADD45a expression within murine lung tissue, and assay murine lungs to determine whether GADD45a knockout alters the expression of inflammatory cytokines such as TNF-a, IL-6, or IL-1(3 compared to controls. Specific Aim #2 will test our hypothesis that GADD45a is a protective factor in ALI by silencing GADD45a in a cell culture model exposed to cyclic stretch or endotoxin, and evaluating the effect on endothelial cell barrier function. We will also explore the dominant mechanistic effect of GADD45a in ALI protection, distinguishing between putative roles in apoptosis regulation and p38 MARK inactivation. These studies will elucidate new insights into ALI pathophysiology, which may generate novel therapeutic targets for this devastating disease. [unreadable] [unreadable] [unreadable]