. This proposal will test the hypothesis that excessive production of blood coagulation factor fibrinogen (FBG) and fibrin [henceforth referred to as fibrin(ogen)] in the lung during PCP may exacerbate damage and result in aggravated lung disease. The long range goal of the research is to elucidate the molecular mechanisms involved in inflammatory processes that modulate FBG gene expression and fibrin(ogen) production during the host response to PCP.
The specific aims are: 1. To elucidate the events leading to increased FBG gene (Aa/BB/g) expression in lung during PCP using a ferret model of PCP (sections a,b,d) and a SCID mouse model (section c).
This aim will include assessment of the following: coordinate versus dyscoordinate expression of the FBG Aalpha, BBeta and gamma mRNAs; expression of FBG and IL-6 mRNA with progression of PCP (ferret model) and resolution of PCP (SCID mouse model); and induction of lung specific FBG gene expression with systemic inflammation. 2. To investigate the molecular mechanisms of FBG gene expression in the lung [ferret model and A549 bronchoalveolar cell cultures BEC)] focusing on the transcriptional rate of the FBG gene. 3. To determine whether the elevated expression of FBG mRNAs in lung results in translation of intact FBG protein in vivo (by immunoelectron microscopy) and in primary BEC and A549 cells. 4. To assess the functional significance of lung epithelial cell-derived FBG. The investigator believes that the study of the mechanisms of FBG gene expression and fibrin(ogen) production in lung tissue during an inflammatory response associated with PCP will provide a broader understanding of the role of fibrin(ogen) in both homeostasis and hemostasis, and may lead to improvements in the management of PCP and other lung inflammatory diseases.
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