Our long range goal remains performing experiments that help elucidate the regulation of alveolar turnover (formation and loss) in the hope this information might be therapeutically useful. Our past, and proposed, work are most relevant to chronic obstructive pulmonary disease (COPD), a disease mainly of midlife and later, and to bronchopulmonary dysplasia (BPD), a condition of very prematurely born babies. COPD is characterized, in part, by the progressive, unremittent destruction of alveoli that is very poorly understood, mechanistically understudied, and at present, unstoppable. BPD is a condition in which arrested alveolus formation is a key factor. In humans, there is neither a means of slowing alveolar loss, nor of inducing alveolus formation. Therefore, this proposal has two major goals: 1. developing a mechanistic understanding of the molecular basis of alveolar destruction (Specific aim 1), and 2. identifying therapeutically safe means of inducing alveolus formation (Specific aim 2 and 3).
Specific aim 1 will investigate the molecular mechanism of alveolus destruction by calorie restriction, which occurs without loss of lung tissue elastic recoil and is regulated by the organism, and of elastase induced alveolar destruction, which occurs with loss of elastic tissue recoil, and is not regulated by the organism. Alveolar destruction during calorie restriction can be followed by nonpharmacologically induced alveolar regeneration; elastase-induced alveolar destruction is not followed by nonpharmacological alveolar regeneration.
Specific aim 2 will test the hypothesis that erythropoietin, which increases alveolus formation in young adult rats (Preliminary Data), has receptors in human fetal lung, and whose serum concentration is low in prematurely born children, protects against hyperoxia inhibition of alveolus formation in newborn rats.
Specific aim 3 will test the hypothesis that all-trans retinoic acid, and estrogen, which induce alveolus formation when given systemically, will do the same when given intranasally in lung surfactant but with no, or fewer, molecular changes in other organs. The proposed studies will be carried out on wild type mice and rats and will utilize lung gene profiling, bioinformatics, unbiased morphometric procedures, and a technical advance that allows easy, noninvasive, modulation of specific gene expression in a lung specific manner. We think our preliminary data, including the ability to alter gene expression of specific genes in a simple, noninvasive, lung specific manner, our extensive experience with morphometry, and now with lung gene profiling, will allow us to successfully complete the work.
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