Chromosomal and Hormonal Contributions to Sex Differences in Ischemic Stroke.

染色体和激素对缺血性中风性别差异的影响。

• 批准号: 8584329
• 负责人: Louise D. McCullough
• 金额: $ 47.41万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-22 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584329
• 关键词: Accounting; Acute; Adult; Age; Aging; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Biological; Brain; Caspase; Cell Culture Techniques; Cell Death; Cell Death Induction; Cerebrum; Chronic; Clinical Research; Clinical Trials; Cytochromes; DNA Damage; DNA Repair Enzymes; Data; Databases; Disease; Dissociation; Economic Burden; Elderly; Elderly woman; Embryo; Environment; Estrogens; Event; Failure; Female; Funding; Genetic; Genotype; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Hormonal; Hormones; Hypoxia; Immune response; Incidence; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; International; Investigation; Ischemic Stroke; Longevity; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Neonatal; Neurons; Neuroprotective Agents; Nitric Oxide; Outcome; Ovarian hormone; Pathway interactions; Patients; Pattern; Peroxonitrite; Phenotype; Poly(ADP-ribose) Polymerases; Prevention; Progestins; Public Health; Recovery; Relative (related person); Sex Characteristics; Sex Chromosomes; Stroke; Testing; Testis; Tissues; Woman; Work; Y Chromosome; aged; apoptosis inducing factor; autosome; brain cell; clinically relevant; cytochrome c; disability; drug efficacy; functional outcomes; improved; juvenile animal; male; men; mortality; neuronal survival; post stroke; reproductive hormone; research study; response; sex; sexual dimorphism; sry Genes; therapeutic target

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.

描述（申请人提供）：临床上，缺血性脑卒中被认为是一种两性二型疾病。大多数国际数据库一致表明，直到老年，女性中风发病率相对于男性较低。然而，与同龄男性相比，老年女性一旦发生中风，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，这种影响在女性中更为明显。生殖激素显然导致了男性和女性病理生物学上的这种差异，然而，激素环境并不能完全解释缺血性性别二型性，因为诱导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有所不同。我们将利用基因操作（“四核心基因型”）小鼠来分离染色体性别与性腺激素对幼年动物中风结局的影响（目的1）；确定控制新生儿激素水平对成人梗死损伤的影响（目的2）；并通过建立脑卒中中动脉闭塞（MCAO）模型，研究性别和激素对4CG小鼠脑卒中后炎症的影响（目的3）。该建议的总体目标是确定遗传和激素（组织和激活效应）在整个生命周期中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重要的翻译相关性，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显示药物对男性和女性患者的疗效不同，开发“性别特异性”治疗靶点可能会提高我们治疗男女卒中患者的能力。