Chromosomal and Hormonal Contributions to Sex Differences in Ischemic Stroke.

描述(申请人提供)：临床上，缺血性中风被认为是一种性二型性疾病。大多数国际数据库一致表明，女性在老年之前的中风发病率低于男性。然而，与年龄匹配的男性相比，一旦中风发生，老年女性的发病率和死亡率更高。衰老增强了对中风的炎症反应，最近的数据表明，这种影响在女性中明显更明显。生殖激素明显导致了男性和女性的这种病理生物学差异，然而，激素环境并不能完全解释缺血性二形性，因为诱发中风后的组织损伤和功能结果除了激素环境外，还受到生物性别的影响。新出现的数据表明，触发细胞死亡的机制在男性和女性中不同。我们将利用基因操作(“四个核心基因型”)小鼠来分离染色体性别和性腺激素对幼年动物中风结局的影响(目标1)；确定操纵新生儿激素水平对成年脑梗塞损害的影响(目标2)；并使用已建立的中风大脑中动脉阻塞(MCAO)模型，研究性别和激素对4CG小鼠中风后炎症的影响(目标3)。这项建议的总体目标是确定遗传和荷尔蒙(组织和激活效应)在整个生命周期内对中风敏感性的贡献。性别选择性细胞死亡机制的鉴定具有显著的翻译相关性，因为对一种性别有效的神经保护剂可能会加剧另一种性别的损伤。由于最近的临床试验表明，药物对男性和女性患者的疗效各不相同，开发针对性别的治疗靶点可能会提高我们治疗中风患者的能力，无论男女。

DESCRIPTION (provided by applicant): Clinically, ischemic stroke is recognized as a sexually dimorphic disease. Most international databases consistently demonstrate that women have lower stroke incidence relative to men until advanced age. However, elderly women have higher morbidity and mortality compared to age-matched men once a stroke occurs. Aging enhances the inflammatory response to stroke, and recent data demonstrate that this effect is significantly more pronounced in females. Reproductive hormones clearly contribute to such differences in male and female pathobiology, however, the hormonal environment does not fully account for ischemic sexual dimorphism as tissue damage and functional outcome after an induced stroke are influenced by biologic sex in addition to the hormonal milieu. Emerging data has shown that the mechanisms that trigger cell death differ in males and females. We will utilize genetically manipulated ("Four Core Genotype") mice to dissociate the effects of chromosomal sex from that of gonadal hormones on stroke outcome in young animals (Aim 1); determine the effect of manipulating neonatal hormone levels on adult infarct damage (Aim 2); and investigate sex and hormone contributions to post-stroke inflammation in the 4CG mice (Aim 3) using a well established middle cerebral artery occlusion (MCAO) model of stroke. The overall goal of this proposal is to determine the genetic and hormonal (organizational and activational effects) contributions to stroke sensitivity across the lifespan. Identification of sex selective cell death mechanisms has significant translational relevance, as neuroprotective agents that are efficacious in one sex may exacerbate injury in the other. As recent clinical trials have shown variable efficacy of drugs in male and female patients, developing "sex- specific" therapeutic targets may improve our ability to treat stroke patients of both sexes.