The Parathyroid Hormone-related Protein (PTHrP)-null mouse lung fails to alveolize. We hypothesize that PTHrP expression and amplification are necessary for lung development, stability and repair. Our long-term goal is to determine the cell/molecular basis of lung morphogenesis. Mechanistically, during the pre-alveolar pseudoglandular phase of lung development epithelial PTHrP up-regulates flbroblast FGF-10, stimulating epithelial Sonic Hedgehog (Shh) amplification of PTHrP. PTHrP signaling consequently down-regulates fibroblast Wnt signaling (by stimulating Protein Kinase A), up-regulating lipofibroblast (LIF) differentiation particularly PTHrP receptor expression, further amplifying PTHrP signaling for type II cell differentiation.
In Aim 1 we hypothesize that deleting PTHrP expression will prevent the up-regulation of FGF-10 and Shh needed for LIF promotion of alveolar development. We further hypothesize that conditional re-expression of PTHrP, which determines the LIF phenotype, will 'rescue' alveolization in the null mouse.
In Aim 2 we hypothesize that deleting PTHrP signaling in the null adult mouse lung will induce myofibroblast (MYF) differentiation, causing interstitial fibrosis. We will determine if conditional re-expression of PTHrP can prevent MYF differentiation and interstitial lung fibrosis. We will use a hierarchical approach to test these hypotheses, including immunohistology, in situ hybridization, Real Time RT-PCR and Western Blotting of whole lung; morphometry combined with Laser Capture Microdissection/Real Time RT-PCR of sectioned lung; and isolated lung cell mRNA transfection, microarray and stable isotope metabolomics. This systematic approach will determine if PTHrP determines lung alveolar development and pathology through intercellular signaling via the Wnt or PKA pathway. These studies will provide important insights to the pathophysiology and treatment of chronic lung diseases of the newborn and adult alike. ? ?
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