The goal of the proposed research is to determine the mechanisms by which peptide growth factors and transcriptional regulators are integrated to control and direct normal lung development. The transcritptional factor, NKX2.1, iscritical in normal dorso-ventral patterning of the anterior foregut, normal pattern formationduring lung development, differentiation of pulmonary epithelial cell-types and expression of lung-specific genes. The peptide growth factors, EGF, and TGF-beta, provide positive and negative signaling to direct normal lung development. EGF promotes lund morphogenesis and differentiation of pulmonary epithelial cell types. Incontrast, TGF-beta signaling restrains lung development, inhibits cellular differentiation and suppresses lung-specific gene expression. We have found that EGF positively regulates of Nkx2.1. The current proposal is directed at determine the precise function of Nkx2.1 inpatternf ormation and chaarcterization of the role played by positive and negative peptide growth factors in it's regulation. We hypothesize that Nkx 2.1 is required for pattern formation in the anterior foregut and the respiratory epithelium, and it's expression is controlled by positive and negative extracellular signaling.
Four Specific Aims are proposed which are designed to test our hypothesis:
Specific Aim 1 : To determine the function of Nkx2.1 in pattern formation in the anterior foregut.
Specific Aim 2 : To determine the precise mechanismby which Nkx2.1 is positively regulated by EGF. Speicifc Aim 3: To determine the mechanism by which TGF-beta inhibits lung-specific, down- stream targets of Nkx2.1 gene, such as SP-C.
Specific Aim 4 : To determine the functional properties of NKX2.1 isoforms by site directed mutagenesis.
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