The applicant's goal is to further understand transcriptional responses of cells during inflammation. Cells have the capacity to respond to injury during inflammation by elaboration of heat shock genes. The subsequent accumulation of heat shock proteins (hsp) serve multiple functions that confers cellular resistance to unfavorable environments. These functions include protection of newly synthesized polypeptides, disaggregation of damaged proteins, mediation of protein traffic, and provision of molecular brakes for transcription factors. Thus, understanding how heat shock genes are regulated has important implications for clinical interventions designed to enhance cellular repair and to protect cells from inflammation. Activation of the heat shock transcription factor, HSF1, is essential for maximal transcriptional activity. Heat itself stimulates an unknown signaling cascade that leads to HSF1 unfolding, multimerization, and phosphorylation. The thermal-induced response results in a 5-100 fold increase in transcription of the heat shock genes. Because heat causes pleitrophic effects, analysis of the signals mediating activation of HSF1 have been difficult to assess. However, the applicant has found a mediator of inflammation, arachidonic acid, to be a potent inducer of HSF1, thus offering a new approach towards understanding the signals that trigger HSF1 leading to increased heat shock gene expression.
The specific aims are i) to identify the arachidonate-sensitive domain of HSF1 responsible for multimerization and ii) to isolate and characterize an arachidonate-inducible kinase. Information obtained from this program will increase our understanding of how arachidonate modulates gene expression through induction of a specific transcription factor. It also provides the basis for analyzing a broader question of how arachidonate mediates induction and possibly repression of inflammatory genes other than the heat shock genes. By understanding how arachidonate mediates molecular switches, new clinical approaches may be derived to alter gene expression so as to enhance cytoprotection during inflammation.
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