Effect of Chromosomal Sex on Stroke Sensitivity

描述（由申请人提供）：临床上，缺血性卒中被认为是一种两性异形疾病。大多数国际数据库一致表明，女性中风发病率低于男性，直到老年。生殖激素在男性和女性的病理生物学的这种差异，作为丰富的数据表明，雌激素和孕激素改变损伤后的神经元存活在体内和体外。然而，越来越明显的是，激素环境并不能完全解释缺血性两性异形。缺血性损伤后的组织损伤和功能结果除了受激素环境的影响外，还受生物性别的影响。在儿科人群中，卒中的性别差异已得到充分证明;尽管循环激素水平相同，但男孩的卒中发病率和卒中相关残疾率均较高。在新生儿缺氧缺血性脑病的实验模型中也观察到类似的发现）。两性之间中风敏感性的内在生物学差异的最令人信服的证据是，当性类固醇从培养基中去除时，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）中的遗传背景不同。我们假设，缺血性细胞死亡的基本机制不同，在男性和女性的基础上的染色体互补。我们将测试这一假设的结果，在两个最近开发的小鼠品系，有一个单一的X染色体（X 0）继发于减数分裂不分离。将39，XO小鼠与40，XX和40 XY同窝小鼠进行比较，以提供X连锁基因剂量效应的数据。将在XX、XO和XY小鼠中评价关键X连锁细胞死亡蛋白（X连锁细胞凋亡抑制因子（XIAP）和细胞凋亡诱导因子（AIF）），以确定第二条X染色体对缺血敏感性的贡献。 公共卫生相关性：在过去的五年中，数据显示，缺血损伤后激活的基本细胞死亡机制受到生物性别的强烈影响。性染色体（XX与XY）对卒中敏感性的贡献尚不清楚，但可以部分解释卒中发病率和结局的显著性别差异。我们假设，缺血性细胞死亡的基本机制不同，在男性和女性的基础上的染色体互补。我们将评估继发于减数分裂不分离的单个X染色体（XO）小鼠的卒中结局。将39，XO小鼠与40，XX和40，XY同窝小鼠进行比较，以提供X连锁基因剂量效应的数据。

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.