GENDER DIFFERENCES IN STROKE

女性患心血管疾病的风险低于男性，包括 中风，但脑缺血事件确实发生在所有年龄的男女。 血管活性激素，雌激素，历来被认为是 但目前尚不清楚类固醇是否对冠心病有保护作用， 也是女性或男性重要的神经保护剂。最 重要的是，女性和男性对组织的相对脆弱性 一旦中风正在进行仍然未知。我们的初步发现， 动物的局灶性脑缺血，以及之前的全球数据 减少脑血流量，清楚地表明，女性有更好的 中风后的结果比男性，缺血性事件可以改变 通过脑血管和大脑的雌激素引发。而 由雌激素提供的保护在生物学上是可行的，特异性的， 神经保护机制是未知的，可能包括 本研究的总体目的是 确定是否有内在的性连锁损伤机制，在挽救 脑缺血事件后的脑组织。在目标1中，我们将确定 局灶性脑缺血后组织病理学和神经行为学结果 （大脑中动脉闭塞，MCAO）在女性中更有利 与雄性大鼠相比，如果内源性雌激素是 神经保护在目标2中，我们将研究内源性和外源性 雌激素通过血管机制改变缺血性结局， 雌激素受体-蛋白激酶G介导的信号通路 随后激活血管平滑肌钙依赖性K 渠道第三个目标将确定MCAO的损伤是否加重 在雌激素受体（雌激素受体）缺陷的转基因小鼠中， 敲除）。在目标4中，我们研究了一种神经机制，假设 雌激素通过bcl-2介导的机制减轻缺血性神经元损伤 它依赖于核雌激素受体。拟定的研究将 有助于我们了解女性脑血管疾病， 雌激素作为一种潜在的神经保护疗法的作用 任何性别。

Women are at a lower risk than men for cardiovascular disease, including stroke, yet cerebral ischemic events do occur in both sexes at all ages. The vasoactive hormone, estrogen, has historically been considered to be protective in coronary heart disease, but it is not clear if the steroid is also an important neuroprotectant in either women or men. Most critically, the comparative vulnerability of females and males to tissue once stroke is ongoing remains unknown. Our preliminary findings with focal cerebral ischemia in animals, as well as previous data with global reduction of cerebral blood flow, clearly suggest that females have better outcomes after stroke than males and that ischemic events can be altered by estrogen-priming of the cerebral vasculature and of brain. While protection conferred by estrogen is biologically feasible, specific neuroprotective mechanisms are unknown and potentially include both vascular and neuronal actions the overall purpose of this study is to determine if there are inherent sex-linked injury mechanisms in salvaging brain tissue after an ischemic event. In Aim 1, we will determine if histopathological and neurobehavioral outcomes after focal ischemia (middle cerebral artery occlusion, MCAO) are more favorable in female versus male rats and if endogenous estrogen is the source of neuroprotection. In Aim 2, we will examine if endogenous and exogenous estrogen alter ischemic outcomes by a vascular mechanism, focusing on a estrogen receptor-protein kinase G mediated signaling pathway with subsequent activation of vascular smooth muscle calcium dependent K channels. The third aim will determine if injury from MCAO is exacerbated in transgenic mice deficient in estrogen receptors (estrogen receptor knock-outs). In Aim 4, we examine a neuronal mechanism, hypothesizing that estrogen reduces ischemic neuronal injury by a bcl-2 mediated mechanism which is dependent on nuclear estrogen receptors. The proposed study will contribute to our understanding of cerebrovascular disease in females and the role of estrogen as a potential neuroprotective therapy for patients of either sex.