Effect of Chromosomal Sex on Stroke Sensitivity

染色体性别对中风敏感性的影响

• 批准号: 8072010
• 负责人: Louise D. McCullough
• 金额: $ 22.63万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072010
• 关键词: Accounting; Apoptosis; Apoptotic; Biological; Blood Vessels; Brain; Caspase; Cell Culture Techniques; Cell Death; Cell Nucleus; Cells; Childhood; Childhood stroke; Clinical Research; Complement; Cytochromes; DNA Damage; DNA Repair Enzymes; Data; Databases; Disease; Elderly; Environment; Estrogens; Event; Exhibits; Experimental Models; Female; Gene Dosage; Genetic; Genetic Nondisjunction; Gonadal Steroid Hormones; Hormonal; Hormones; In Vitro; Incidence; Injury; International; Ischemia; Ischemic Stroke; Lead; Link; Mediating; Meiosis; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Neonatal; Neurons; Nitric Oxide; Outcome; Pathway interactions; Peroxonitrite; Phenotype; Poly(ADP-ribose) Polymerases; Population; Progestins; Proteins; Regulation; Relative (related person); Research Personnel; Risk; Secondary to; Sex Characteristics; Sex Chromosomes; Shapes; Specificity; Stroke; Testing; Tissues; Turner' s Syndrome; Vascular Diseases; Woman; X Chromosome; apoptosis inducing factor; base; boys; disability; functional outcomes; human BIRC4 protein; in vivo; male; men; neonatal hypoxic-ischemic brain injury; neuronal survival; pro-apoptotic protein; public health relevance; reproductive hormone; research study; response; sex; sexual dimorphism

DESCRIPTION (provided by applicant): Clinically, ischemic stroke is recognized as a sexually dimorphic disease. Most international databases consistently demonstrate that women enjoy a lower stroke incidence relative to men until advanced age. Reproductive hormones contribute to such differences in male and female pathobiology, as a wealth of data show that estrogens and progestins alter neuronal survival after injury both in vivo and in vitro. However, it is becoming increasingly evident that the hormonal environment does not fully account for ischemic sexual dimorphism. Tissue damage and functional outcome after ischemic damage are shaped by biologic sex in addition to the hormonal milieu. Sex differences in stroke have been well documented in pediatric populations; both stroke incidence and stroke-related disability are higher in boys despite equivalent levels of circulating hormones. Similar findings are seen in experimental models of neonatal hypoxic- ischemic encephalopathy). The most convincing evidence for intrinsic biological differences in stroke sensitivity between the sexes is that sex-specificity can also be modeled in cell culture when sex steroids are removed from the media. One of the new concepts that must be considered is that stroke operates in a different genetic background in females (XX) and males (XY). We hypothesize that basic mechanisms of ischemic cell death differ in males and females based on the chromosomal complement. We will test this hypothesis by examining outcome in two recently developed mouse strains that have a single X chromosome (X0) secondary to meiotic non-disjunction. The 39, XO mice will be compared to 40, XX and 40 XY littermates to provide data on X-linked gene dosage effects. Key X-linked cell death proteins (X linked inhibitor of apoptosis (XIAP) and Apoptosis Inducing Factor (AIF)) will be evaluated in XX, XO and XY mice to determine the contribution of the second X chromosome to ischemic sensitivity. PUBLIC HEALTH RELEVANCE: Over the past five years, data are emerging that basic cell death mechanisms activated after ischemic insults are strongly influenced by biological sex. The contribution of the sex chromosomes (XX vs. XY) to stroke sensitivity is not known, but could account in part for the dramatic sex differences seen in stroke incidence and outcome. We hypothesize that basic mechanisms of ischemic cell death differ in males and females based on the chromosomal complement. We will evaluate stroke outcome in mice with a single X chromosome (XO) secondary to meiotic non-disjunction. The 39, XO mice will be compared to 40, XX and 40, XY littermates to provide data on X-linked gene dosage effects.

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，女性中风的发病率相对于男性要低。生殖激素导致了男性和女性病理生物学的差异，大量数据表明，雌激素和黄体酮在体内和体外都能改变损伤后的神经元存活。然而，越来越明显的是，荷尔蒙环境并不能完全解释缺血性两性二态性。除了激素环境外，缺血损伤后的组织损伤和功能结果还受生物性别的影响。在儿科人群中，中风的性别差异已被充分记录；尽管循环激素水平相当，男孩的中风发病率和中风相关残疾都更高。在新生儿缺氧缺血性脑病的实验模型中也发现了类似的结果。最令人信服的证据是，当从培养基中去除性类固醇时，性别特异性也可以在细胞培养中建模。必须考虑的一个新概念是，中风在女性（XX）和男性（XY）中具有不同的遗传背景。我们假设，基于染色体补体，男性和女性缺血性细胞死亡的基本机制不同。我们将通过检测两种新近开发的小鼠品系的结果来验证这一假设，这两种小鼠品系具有单个X染色体（X0），继发于减数分裂不分离。39，xo小鼠将与40，XX和40 XY窝鼠进行比较，以提供x连锁基因剂量效应的数据。将在XX、XO和XY小鼠中评估关键的X连锁细胞死亡蛋白（X连锁细胞凋亡抑制剂（XIAP）和凋亡诱导因子（AIF）），以确定第二条X染色体对缺血敏感性的贡献。