Although there is increasing evidence that failure of normal lung septation is a component of bronchopulmonary dysplasia (BPD) currently seen in small premature infants, a fibroproliferative response remains responsible for many of the untoward alterations in pulmonary function. While the pathogenic mechanisms underlying this response are complex, it is likely that many of the harmful aspects are mediated by the manifold effects of TGF-B as a final common pathway. Strong evidence suggests that many of the effects of TGF-B on fibroblast proliferation and extracelluar matrix production are mediated by connective tissue growth factor (CTGF). The preliminary data demonstrate that CTGF expression by cultured human fetal lung fibroblasts and airway smooth muscle cells is greatly stimulated by TGF-B1 and that CTGF is expressed in the developing lung. The investigators propose the following hypotheses: (1) A TGF-B superfamily member stimulates the expression of CTGF which acts as a downstream mediator in the regulation of branching and other morphologic events during normal lung development. (2) The signaling pathway by which TGF-B up-regulates CTGF expression involves cellular components in addition to the Smads. (3) CTGF is a major effector molecule in the pathogenesis of pulmonary fibrosis seen in BPD. To test these hypotheses, they will: (1) Determine the temporal and spatial expression of CTGF in the developing mouse and human lung and determine its potential role in lung development by conditional ablation. (2) Define the signaling pathway and mechanisms whereby TGF-B1 up-regulates the expression of CTGF and modulates expression of matrix proteins. (3) Develop strategies for inhibiting the fibrotic response mediated by TGF-B and CTGF. This work will be carried out in close collaboration with Projects 5 & 6, will interact significantly with Projects 1 and 4, will utilize the Tissue Culture Core for the implementation of the mouse lung bud model and will obtain human lung samples from the Clinical Core. Identification of the mechanisms of action of CTGF and the pathways regulating its expression are of considerable importance, since CTGF may play a key role in normal lung development and blocking its abnormal production may ameliorate the fibrotic response seen in BPD.
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