There continues to be a need for the development of novel therapeutic strategies to attenuate acute lung injury in clinical medicine. Heat shock protein-70 (HSP-70) is an intracellular protein that confers protection against diverse forms of cellular injury. The central hypothesis of this research application is that increased expression of HSP-70 in distal respiratory epithelium will protect against acute lung injury. To directly test this hypothesis, the applicant will generate transgenic mice expressing HSP-70 in a lung specific manner. Lung specific HSP-70 expression will be achieved by placing the human HSP-70 cDNA under the control of promoter elements that direct expression of heterologous proteins to specific subsets of distal respiratory epithelium. The applicant will determine: 1) the effects of increased HSP-70 expression on lung development and function, 2) if increased expression of HSP-70 protects against acute lung injury, 3) the spatial determinants of protection, and 4) the effects of increased HSP-70 on injury-associated lung inflammation and surfactant dysfunction. Long term, these data will form the basis for future studies directed towards the use of HSP-70 expression as a therapeutic strategy to attenuate acute lung injury in the clinical setting. The principal investigator is currently an Assistant Professor of Pediatrics in the Division of Critical Care Medicine, Department of Pediatrics. The Mentored Clinical Scientist Development Award will allow the principal investigator to continue his development as a clinician-scientist. The research environment presents an extraordinary opportunity because of the many successful independent investigators in the fields of pulmonary biology and lung injury at this institution. The experimental design in this application includes challenging goals. The information gained will contribute positively to knowledge regarding protective strategies against acute lung injury.
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