Role of Estrogen and Angiogenesis in Stroke Prevention.

雌激素和血管生成在中风预防中的作用。

• 批准号: 7275890
• 负责人: AGNIESZKA ANNA ARDELT
• 金额: $ 13.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-02 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275890
• 关键词: Adenoviridae; angiogenesis; angiopoietins; biological signal transduction; cytochrome P450; estrogens; gene delivery system; gene expression; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; microinjections; neuropharmacology; neuroprotectants; pharmacokinetics; stroke; transfection /expression vector; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Ischemic stroke is a major health problem in the U.S. Estrogen is neuroprotective in experimental stroke. Clinical trials of hormone replacement (HR) have shown worse outcomes in patients randomized to HR. Although the adverse effects of HR may be due to progesterone, few effective therapies for stroke are available; therefore, it is critical to delineate the downstream effectors of estrogen mediated (EM) neuroprotection in order to maximize protective effects while minimizing harmful side effects. We have linked estrogen treatment to modulation of angiopoietin-1 (ang-1) mRNA and augmentation of cerebral capillary density in rodent brain. This application proposes to study the consequences of EM ang-1 mRNA augmentation in brain and the effects of therapeutic cerebral angiogenesis with ang-1 and vascular endothelial growth factor (VEGF) in an experimental stroke model. Specific Aims: 1) To delineate the consequences of EM ang-1 mRNA expression in brain by: a) evaluating the localization of ang-1 mRNA and protein expression; b) quantifying ang-1 protein; c) determining the effect of ang-1 on cell signaling; d) evaluating the vascular network's capillary anatomy and permeability, endothelial cell proliferation, apoptosis, and anastomotic architecture. 2) To determine if blocking ang-1 function in vivo attenuates EM neuroprotection. 3) To determine if chronic pre-ischemic treatment with ang-1, or ang-1 with VEGF, alters the microvascular network and offers stroke protection. Methods: Ovariectomized female rats treated with placebo or estrogen and male rats will be used. Gene delivery will be accomplished using adenoviral vectors and intracerebral, as well as intravenous, injection. A transient focal cerebral ischemia model in rats and histological and molecular analyses will be used. Summary: This grant will elucidate the role of estrogen in cerebral angiogenesis and neuroprotection and will investigate therapeutic cerebral angiogenesis as a means of stroke prevention.

描述（由申请人提供）：缺血性中风是美国雌激素的主要健康问题，在实验性中风中是神经保护作用。激素替代（HR）的临床试验在随机分为HR的患者中表现出较差的预后。尽管人力资源的不良影响可能是由于孕激素引起的，但很少有有效的中风疗法。因此，至关重要的是描述雌激素介导（EM）神经保护的下游效应子，以最大程度地提高保护作用，同时最大程度地减少有害副作用。我们已经将雌激素治疗与调节血管生成素-1（Ang-1）mRNA的调节以及啮齿动物脑中脑毛细血管密度的增强。该应用建议在实验性中风模型中研究EM ANG-1 mRNA增强在大脑中的后果以及ANG-1和血管内皮生长因子（VEGF）的治疗性脑血管生成的影响。具体目的：1）通过以下方式描述EM ANG-1 mRNA表达的后果：a）评估ANG-1 mRNA和蛋白质表达的定位； b）量化Ang-1蛋白； c）确定ANG-1对细胞信号传导的影响； d）评估血管网络的毛细血管解剖结构和渗透率，内皮细胞增殖，凋亡和吻合式结构。 2）确定阻断Ang-1在体内功能是否会减弱EM神经保护。 3）确定用Ang-1或VEGF Ang-1的慢性缺血前治疗会改变微血管网络并提供中风保护。方法：使用安慰剂或雌激素和雄性大鼠治疗的卵巢切除雌性大鼠。基因递送将使用腺病毒载体和脑内以及静脉注射来完成。将使用大鼠的瞬时局灶性脑缺血模型，并将使用组织学和分子分析。摘要：该赠款将阐明雌激素在脑血管生成和神经保护中的作用，并将研究治疗性脑血管生成作为预防中风的一种手段。