Dr. Mackman's hypothesis is that induction of tissue factor (TF) gene expression in monocytes is regulated at the level of transcription and that inhibition of transcription factors and coactivators that mediate induction will prevent cell surface TF expression. The proposal contains 4 Specific Aims: 1) to test the hypothesis that c-Rel regulates inducible gene expression in monocytes by interaction with coactivators., 2) To elucidate how all - trans retinoic acid (ATRA) selectively inhibits LPS induction of TF gene expression in monocytes. 3) To test the hypothesis that c-Rel/p65 is required for LPS induction of TF gene expression in living animals. 4) To test the hypothesis that inhibition of NF-KB proteins will prevent lethality in a novel mouse sepsis model. The applicant will identify coactivators by screening CDNA libraries with the C-terminus of c-Rel. The applicant will examine retinoic acid inhibition in cultured monocytic cells. Analysis of the role of c-Rel/p65 in vivo will employ a c-Rel -/- mice and transgenic mice containing a human TF minigene. Finally the applicant will use proteasome inhibitors to block NF-(B /Rel activity in a novel mouse sepsis model humanized for TF.
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