) BPD is a disease that affects the structural and functional organization of the lung. Homeodomain transcriptional factors are thought to play a role in structural organization and cytodifferentiation of tissues during development. The investigators have used baboon RNA to clone a number of cDNAs that encode TTF-1, a homeodomain transcriptional regulator. They propose a model in which alternative morphogenetic signals released by tissue injury lead to alterations in spatiotemporal regulation of TTF-1, derailment of normal lung organogenesis and the consequent structural and functional aberrations characteristic of BPD. three observations form the logical basis for this application: 1)Inhibition of TTF-1 translation by antisense oligonucleotides results in suppression of branching morphogenesis (a striking structural abnormality) and epithelial dysplasia (Minoo et al, 1995), 2) TTF-1 is extinguished in atelectatic and fibrotic regions of the human BPD lung samples (Stahlman et al., 1995), and 3) BPD in the baboon is characterized by structural aberrations that include reduced alveolar surface area/number, and epithelial dysplasia (Coalson et al., 1995). Because TTF-1 is expressed in both fetal and adult lung cells, they postulate that TTF-1 is necessary throughout lung development as a key regulator of the structural organization of the lung and differentiation and maintenance of the specialized lung epithelial cell types (e.g., alveolar type II cells). To determine the role of TTF-1 in BPD they propose the following hypothesis; because the phenotypic characteristics of BPD are consistent with alterations in the structural organization of the lung and epithelial dysplasia, they hypothesize that spatiotemporal alterations in the expression of TTF-1 induced by epithelial cell injury result in abnormal structural organization of the injured lung in premature baboon neonates. Accordingly experiments are proposed to determine the role of TTF-1 by studying it's expression, distribution and regulation in the baboon model of prematurity and BPD.
