The long term goal of this project is to elucidate how surfactant secretion is regulated. The focus in the next funding period well be on signal- transduction mechanisms, protein phosphorylation steps and regulation of genes involved in phosphatidylcholine (PC) secretion in type II cells isolated from newborn and adult rats. Surfactant secretion is a highly regulated process; several physiological and pharmacological agents stimulate surfactant PC secretion and there is considerable information on the signal-transduction mechanisms involved. A number of receptors, the effector enzyme to which they are coupled, second messengers generated by those enzymes and protein kinases that are finally activated have been identified. There is evidence of a lest three different signaling mechanisms. At least one secretagogue, ATP the prototypical P2 purinoceptor agonist, acts by all three s well s possibly additional signaling mechanisms. Some of the questions that remain unanswered include th following; How is the effect of ATP mediated? Does it act at an adenylate cyclase-coupled receptor other than the adenosine A2 receptor? Does it also act at a second P2 receptor distinct from P2u? Are the stimulatory effects of ATP early in development, when the P2u agonist UTP does not stimulate secretion, mediated by such receptors(s)? Are there developmental changes in the expression of secretagogue receptor genes: What proteins are phosphorylated by the different protein kinases involved in PC secretion? What proteins are phosphorylated by the different protein kinases involved in PC secretion? Is there agonist specificity in protein phosphorylation? Do hormones accelerate development of the surfactant secretory systems? Five specific aims are proposed to address those and related questions. 1. Elucidate the signaling mechanism(s) by which ATP stimulates PC secretion in the immediate postnatal period. 2. Establish the developmental profile of expression of surfactant secretagogue receptor genes. 3. Determine the protein phosphorylation pattern in type Ii cells i response to PC secretagogues. Determine if it agonist specific and regulated developmentally. 4. Determine if hormones accelerate development of the secretory signal-transduction mechanisms. The focus will be on hormones that accelerate fetal lung maturation and stimulate surfactant production in fetal lung. 5. Determine if there is a signaling step that is common to different classes of PC secretagogues. Elucidation of the mechanisms regulating surfactant secretion in type II cells should provide a better understanding of the physiological regulation of surfactant metabolism. Such information is critical so that rational therapeutic interventions for prevention and/or control of the respiratory distress syndrome and other lung diseases may be developed.
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