Interferons (IFNs), a family of cytokines with diverse biological functions, including anti-tumor and immunomodulatory actions, are a crucial component of a network of regulatory substances which maintain homeostasis for multicellular organisms. The overall goal of the Program Project is to develop a comprehensive account of signaling in the IFN system from receptors to genes. IFNs bind specific cell surface receptors, eliciting signals which culminate in transcriptional activation of a set of genes, termed IFN-stimulated genes (ISG), which encode proteins believed to be the biological effectors of IFN treatment. The current level of understanding of IFN(alpha) has been achieved by the application of biochemistry, genetics, and molecular biology, to which our group has made substantial contributions. The Program Project is composed of six research projects, a Tissue Culture Core, and a centralized Administrative Core. The individual proposals are highly focused but are well integrated into an overall research plan. We propose to use genetic experimental approaches to complement traditional biochemical and molecular biologic methods to isolate and characterize the components of signaling pathways, as reflected in the research proposals of the individual investigators and by the overall plan of the Program Project. Project 1 is directly focused on the genetic approach to signaling, including the generation of mutant cell lines selectively deficient for IFN signaling and development of techniques for rapidly complementing these mutants. Signaling components will be functionally analyzed, partially through the use of defective cell lines and extracts prepared from such cells. In Project 2, these techniques will be extended to address ISGF3-independent signaling pathways. Project 3 addresses signaling crosstalk between IFN(gamma) and TGFBetaI. Project 4 proposes a strategy for abrogating expression of specific genes, using an antisense-targeted, IFN-inducible endoribonuclease strategy. This approach will have obvious applicability for selected experiment in other projects. Project 5 is directed at the mechanisms through which dsRNA can induce both IFN sensitive and insensitive genes. Project 6 is focused upon the role of Rel homology genes and kappa(B) sequence motifs in mediating response to IFN(gamma) and LPS. The components of this Program Project are complementary, by virtue of their relation to the major themes of the program, their interactive nature, and, administratively, by their use of the common facilities house in the Cores.
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