Alveolar epithelial cells (AEC) exist in the adult lung as two highly differentiated phenotypes (AEC 1 & 2) with numerous specialized functions, which do not normally divide. Yet, both during embryonic and fetal life, and during the repair of alveolar epithelial injury, AEC proliferate. Moreover, transformed AEC proliferate aggressively in adenocarcinoma of the lung. The molecular switches that determine the proliferative and nonproliferative phenotypes of normal and malignant AEC are incompletely understood. During Years 01-03 we completed the previous specific aims by characterizing several specific second messenger and protein phosphorylation mechanisms that regulate surfactant secretion in ABC2. We also extended our developmental protein phosphorylation aims to include candidate genes that may control stage-specific proliferation and differentiation of AEC, including cyclin D2, cyclin-dependent protein kinase 1 (cdk1), and transcription factors of the Id family. Thus, in this competitive renewal we plan studies in fetal and adult rat AEC and in transformed AEC lines to test the following. Hypothesis: developmental stage-specific transcriptional regulation of cell cycle control genes determines the proliferation and differentiation phenotypes of AEC during lung development, repair of injury, and transformation. The following Specific Aims are designed to test this hypothesis:
Aim 1. To identify developmental stage-specific cell cycle control gene (cyclin and cdk) expression during normal AEC development and transformation.
Aim 2. To define cyclin and cdk gene expression in adult AEC2 following hyperoxic lung injury and recovery, a model of re-induced AEC2 proliferation.
Aim 3. To determine the developmental function of cyclin and cdk gene expression in AEC using (i) transforming growth factor beta, (ii) antisense oligodeoxynucleotides and (iii) episome-based antisense constructs with inducible promoters.
Aim 4. To define (i) the transcriptional regulation of key cell cycle control gene promoters (cyclin D2 and cdk1) and (ii) the role of Id family transcription factors in AEC. Future Aims: To analyze transcriptional mechanisms and function of pulmonary development specific transcription factor genes. Clinical relevance: To provide the basis for novel therapeutic approaches to lung development, lung injury repair, and prevention or treatment of lung cancer.
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