Role of Egr-1 in post-stroke inflammation & brain damage

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DESCRIPTION (provided by applicant): The role of transcription factors (TFs) in modulating post-ischemic cerebral inflammation is not evaluated in detail. While Egr1 (NGFI-A/Krox24) is a TF that promotes inflammatory gene expression, at least 2 other TFs can control Egr1. Of these, c-EBP-beta can stimulate and PPAR-gamma can inhibit Egr1 induction. We hypothesize that after focal ischemia (1) EgM induction contributes to inflammation and brain damage; (2) c-EBP-beta is an upstream TF that induces Egr1 expression and inflammation; and (3) PPAR-gamma activation can curtail Egr1 induction and inflammation. Preliminary studies showed (a) sustained upregulation of Egr1, c-EBP-beta and PPAR-gamma expression after focal ischemia; (b) smaller infarcts in Egr1 null mice and bigger infarcts in EgM adenoviral transfected rats after focal ischemia, (c) curtailed post-ischemic inflammatory gene expression in EgM null mice, (d) less brain damage, decreased inflammation and less Egr1 induction in c-EBP-beta knockout mice after focal ischemia, and (e) prevention of post-ischemic EgM induction, inflammation and infarction by treatment with PPAR-gamma agonists. Using antisense knockdown, adenovirus-induced overexpression, and null mice, we will evaluate the functional significance and the interactive mechanism of action of these transcription factors in modulating inflammation and neuronal damage after transient focal ischemia in rodent brain. We will study if (a) Egr-1 knockdown prevents and Egr-1 overexpression exacerbates post-ischemic inflammation and brain damage; (b) Ischemia in Egr-1 knockout mice results in less inflammation and smaller infarcts; (c) C-EBP beta knockout mice show curtailed EgM induction, decreased inflammation and less neuronal damage after ischemia; and (d) PPAR-gamma agonists decrease the post-ischemic inflammation and brain damage by preventing EgM induction. The ultimate goal is to define the role of EgM and its regulators to develop therapies to control cerebral inflammation at the level of transcription.