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

描述（由申请人提供）：转录因子（TFs）在调节缺血性脑炎症中的作用未被详细评估。虽然Egr1 （NGFI-A/Krox24）是一种促进炎症基因表达的TF，但至少有2种其他TF可以控制Egr1。其中，c- ebp - β可以刺激Egr1的诱导，ppar - γ可以抑制Egr1的诱导。我们假设局灶性缺血后(1)EgM诱导有助于炎症和脑损伤；(2) c- ebp - β是诱导Egr1表达和炎症的上游TF；(3)激活ppar - γ可以抑制Egr1的诱导和炎症。初步研究显示(a)局灶性缺血后Egr1、c- ebp - β和ppar - γ表达持续上调；(b)局灶性缺血后，Egr1缺失小鼠的梗死面积较小，EgM腺病毒转染大鼠的梗死面积较大，(c) EgM缺失小鼠的缺血后炎症基因表达减少，(d)局灶性缺血后，c- ebp - β敲除小鼠的脑损伤减轻，炎症减轻，Egr1诱导减少，(e) ppar - γ激动剂治疗可预防缺血后EgM诱导、炎症和梗死。通过反义敲除、腺病毒诱导过表达和空白小鼠，我们将评估这些转录因子在调节鼠脑短暂局灶性缺血后炎症和神经元损伤中的功能意义及其相互作用机制。我们将研究是否(a) Egr-1敲低可预防缺血后炎症和脑损伤，而Egr-1过表达可加剧缺血性炎症和脑损伤；(b) Egr-1敲除小鼠缺血后炎症减轻，梗死面积减小；(c) c - ebp β敲除小鼠缺血后EgM诱导减弱，炎症减轻，神经元损伤减轻；(d) ppar - γ激动剂通过阻止EgM诱导减少缺血后炎症和脑损伤。最终目标是确定EgM及其调节因子的作用，以开发在转录水平上控制脑炎症的治疗方法。

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.