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

Egr-1在中风后炎症中的作用

• 批准号: 7037132
• 负责人: Raghu VEMUGANTI
• 金额: $ 25.91万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037132
• 关键词: antisense nucleic acid; autoradiography; brain injury; cerebral artery; cerebral ischemia /hypoxia; gene induction /repression; genetically modified animals; immunocytochemistry; infarct; inflammation; inhibitor /antagonist; laboratory mouse; laser Doppler flowmetry; leukocyte activation /transformation; macrophage; neuroprotectants; neuropsychological tests; neutrophil; oligonucleotides; peroxisome proliferator activated receptor; protein protein interaction; protein structure function; rosiglitazone; spontaneous hypertensive rat; transcription factor; transfection /expression vector

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.

描述（由申请人提供）：转录因子（TF）在调节缺血后脑炎症中的作用未详细评价。虽然Egr 1（NGFI-A/Krox 24）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Egr 1。其中，c-EBP-β可以刺激Egr 1诱导，而PPAR-gamma可以抑制Egr 1诱导。我们假设局灶性缺血后（1）EgM诱导导致炎症和脑损伤;（2）c-EBP-β是诱导Egr 1表达和炎症的上游TF;（3）PPAR-gamma激活可以减少Egr 1诱导和炎症。初步研究表明：（a）局灶性缺血后Egr 1、c-EBP-β和PPAR-gamma表达持续上调;（B）局灶性缺血后，Egr 1缺失小鼠中的梗死较小，EgM腺病毒转染大鼠中的梗死较大，（c）EgM缺失小鼠中缺血后炎性基因表达减少，（d）脑损伤较少，局灶性缺血后c-EBP-β敲除小鼠中炎症减少和Egr 1诱导减少，和（e）通过用PPAR-γ激动剂治疗预防缺血后EgM诱导、炎症和梗塞。使用反义基因敲除，腺病毒诱导的过表达，和空小鼠，我们将评估这些转录因子在调节炎症和短暂局灶性脑缺血后的神经元损伤的作用的功能意义和相互作用机制。我们将研究（a）Egr-1敲低是否预防缺血后炎症和脑损伤，而Egr-1过表达是否加重缺血后炎症和脑损伤;（B）Egr-1敲除小鼠中的缺血是否导致较少的炎症和较小的梗死;（c）C-EBP β敲除小鼠在缺血后是否显示减少的EgM诱导、减少的炎症和较少的神经元损伤;和（d）PPAR-gamma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及其调节剂的作用，以开发在转录水平控制脑炎症的疗法。