Gender Differences in Stroke

中风的性别差异

• 批准号: 7553595
• 负责人: PATRICIA D. HURN
• 金额: $ 22.95万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7553595
• 关键词: Adult; Aging; Androgens; Animals; Aromatase; Aromatase Inhibitors; Brain; Brain Injuries; Cerebral Ischemia; Cerebrovascular Disorders; Cerebrum; Clinical; Cytochrome P450; Data; Diabetes Mellitus; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exhibits; Female; Funding; Gender; Gonadal Steroid Hormones; Hypertension; Incidence; Injury; Invasive; Ischemia; Link; Mediating; Middle Cerebral Artery Occlusion; Molecular; Mus; Neurosurgical Procedures; Outcome; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Play; Progesterone; Property; Purpose; Reperfusion Injury; Research; Risk Factors; Rodent; Role; Sex Characteristics; Signal Transduction; Stanolone; Steroids; Stroke; Testing; Testosterone; Tissues; Work; artery occlusion; in vivo; male; middle age; middle cerebral artery; neuroprotection; novel; receptor; sex

Our previous work emphasizes that tissue outcome from experimental stroke is gender-dependent and influenced by cellular and molecular actions of female and male sex steroids. We have shown that estrogen provides protection from cerebral injury in rodents of both sexes, even in the presence of complicating stroke risk factors such as hypertension and diabetes and in aging animals. The overall purpose of this project is to further examine inherent sex-linked injury mechanisms with emphasis on the role of 17-beta estradiol and on the principal active androgens, testosterone and dihydrotestosterone. Estrogen' s mechanisms of protection are clearly multifactorial and involve both brain and cerebral vessels. Aim 1 will further evaluate the role of estrogen receptor (ER) subtype alpha vs beta in mediating estradiol's neuroprotective mechanisms. Our preliminary data that estradiol treatment can only partially protect ER alpha deficient mice (alphaERKO) from ischemic injury. We will test the hypothesis that estradiol does not protect alphaERKO from middle cerebral artery occlusion (MCAO) as compared to wild type or ER beta deficient (betaERKO) mice. In aim 2, we will evaluate the importance of estrogen's known activation of the PI3-Akt kinase signaling to the steroid' s neuroprotective properties in experimental stroke. The hypothesis is that estradiol treatment reduces delayed damage after MCAO through enhancement of the PI3-Akt pathway activation that ordinarily occurs after ischemia. Aim 3 will determine the contribution of estradiol aromatized from testosterone in brain to neuroprotection from focal cerebral ischemia and examine mice genetically deficient in cytochrome P450 estrogen aromatase vs treated with local brain aromatase inhibitors. Most research aimed at understanding gender differences in experimental or clinical stroke has focused on the potential value of female sex steroids. An equally important issue remains understudied, i.e. if and how androgens alter incidence and outcome from cerebrovascular disease. Aim 4 will determine if testosterone and dihydrotestosterone (DHT) play an important role in outcome from MCAO in adult and middle-aged male animals. Our preliminary data suggest that potent androgens enhance damage in young males but provide protection in middle age-stroke. The importance of androgens to stroke is virtually uncharted territory. These findings will have broad application to patients with brain injury from stroke or reperfusion injury after invasive neurosurgical procedures.

我们以前的工作强调，实验性中风的组织结局依赖性依赖性，受雌性和男性性类固醇的细胞和分子作用的影响。我们已经表明，即使在存在复杂的中风风险因素（例如高血压和糖尿病）以及衰老的动物中，雌激素也可以保护两性啮齿动物的脑损伤。该项目的总体目的是进一步研究固有的 性别连接的损伤机制，重点是17β雌二醇以及主要活性雄激素，睾丸激素和二氢睾丸激素的作用。雌激素的保护机制显然是多因素的，并且涉及大脑和大脑血管。 AIM 1将进一步评估雌激素受体（ER）亚型α与β在介导雌二醇的神经保护机制中的作用。我们的初步数据（雌二醇治疗）只能部分保护ERα缺乏小鼠（αerko）免受缺血性损伤。我们将检验以下假设：与野生型或ERβ缺乏症（Betaerko）小鼠相比，雌二醇不能保护αERPHAERKO免受脑动脉闭塞（MCAO）。在AIM 2中，我们将评估雌激素对PI3-AKT激酶信号的已知激活与实验性中风中类固醇神经保护特性的重要性。假设是雌二醇治疗通过加强通常发生的PI3-AKT途径激活而减少了MCAO后延迟损害 缺血之后。 AIM 3将确定雌激素从脑中的睾丸激素对局灶性脑缺血的神经保护作用的贡献，并检查小鼠在遗传上缺乏细胞色素P450雌激素芳香酶与局部脑芳香酶抑制剂治疗的小鼠。大多数旨在了解实验或临床中风的性别差异的研究都集中在女性性类固醇的潜在价值上。一个同样重要的问题仍在研究，即雄激素是否以及如何改变脑血管疾病的发生率和结果。 AIM 4将确定睾丸激素和二氢睾丸激素（DHT）在成年和中年雄性动物中MCAO的结果中起重要作用。我们的初步数据表明，有效的雄激素增强了年轻男性的损害，但在中间年龄较大的情况下提供了保护。雄激素对中风的重要性实际上是未知的领域。这些发现将在侵入性神经外科手术后因中风或再灌注损伤患有脑损伤患者的广泛应用。