It is not well established that Nkx2.1 is a critical regulator of lung morphogenesis and differentiation of pulmonary specialized epithelial cells. The precise role of NKX2.1 peptide appears to be related to Proximo-Distal lung morphogenesis. Recent data demonstrate that Nkx2.1 is upstream of a battery of morphoregulatory genes. In particular, the gene encoding the signaling molecule BMP4 is undetectable in Nkx2.1(-/-) lungs, as are the ECM protein Collagen type IV and the cellular receptors alpha1, alpha2, and alpha3 integrins. Abrogation of BMP4 signaling by transgenic means results in loss of distal lung structures implicating both Collagen and alpha-integrins in lung branching morphogenesis. The sum of the accumulated data from the last funding period of HL-56590 now provides the opportunity and the rationale to examine the possible functional integration amongst the three classes of transcription factors, signaling molecules and the ECM. In addition, precise spatio-temporal regulation of Nkx2.1 expression is critical to its function, but the in vivo mechanisms remain unknown.
Three specific aims are proposed with the distinct goal of examining the overall hypothesis that developmentally regulated expression of Nkx2.1 directs proximo-distal lung morphogenesis through precise spatio-temporal activation of downstream target genes (e.g. Bmp4, collagen IV and alpha-integrins).
Specific Aim 1 is to characterize the specificity of the Bmp4 pathway in lung morphogenesis.
Specific Aim 2 is to determine the precise regulatory relationship among Nkx2.1, Bmp4, and the ECM (collagen IV and alpha-integrins).
Specific Aim 3 is to determine the regulation of Nkx2.1 gene expression. By the completion of the described studies the authors intend to gain a better understanding of the how morphogenesis and cellular differentiation along the proximo-distal axis of the lung is regulated.
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