This applicant has had a long-standing interest in the biology of the formation of pulmonary alveoli during post-natal development. Recently, he has demonstrated that retinoic acid (RA) not only promotes the post-natal development of alveoli in the rat but also provides remediation of the tissue changes in an experimental model of emphysema in adult rats. To investigate this finding further, his specific aims are: 1) to use differential display (DD) and differential screening, as components of a systematic search for genes that in rat lung have unique and essential functions in the formation of alveoli during RA- abrogation of elastase-induced emphysema. Selected analogous genes will be cloned and """"""""knocked-out"""""""" in mice and morphometric procedures use to determine if there is an alteration of any of the following: a) septation of the gas-exchange region in the newborn mouse; b) the post-septational increase in alveolar number, or c) abrogation of elastase-induced emphysema. 2) To use morphometric procedures to test the hypothesis a) that in rats with elastase-induced emphysema the long's diffusion capacity is diminished but increased after treatment with RA; b) that the RA- induced abrogation of elastase produced emphysema persists after treatment with RA is stopped; and c) that treatment of Tsk mice (which have emphysema due to low serum and lung anti-elastase activity) with RA alone, and with a protease inhibitor, will abrogate the emphysema. We believe our preliminary data and the well documented areas of competence of those involved in this proposal demonstrate the feasibility and likely success of our pursuit of a new paradigm--the pharmacological remediation of emphysema fostered by understanding the molecular basis of alveolus formation.
