Effect of Chromosomal Sex on Stroke Sensitivity

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。生殖激素导致了男性和女性病理生物学上的差异，因为大量数据表明，雌激素和孕激素在体内和体外都改变了损伤后神经元的存活。然而，越来越明显的是，荷尔蒙环境并不能完全解释缺血性二形性。缺血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。中风的性别差异在儿科人群中已经有了很好的记录；尽管循环激素水平相同，但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看到了类似的发现)。性别之间中风敏感性内在生物学差异的最令人信服的证据是，当性类固醇从介质中去掉时，性别特异性也可以在细胞培养中模拟。必须考虑的新概念之一是，中风在女性(XX)和男性(XY)中的遗传背景不同。我们假设，基于染色体补体，缺血性细胞死亡的基本机制在男性和女性中不同。我们将通过检查两个最近开发的小鼠品系的结果来检验这一假设，这两个品系的减数分裂不分离继发于单个X染色体(X0)。39，XO小鼠将与40，XX和40个XY胎进行比较，以提供X连锁基因剂量效应的数据。将在XX、XO和XY小鼠身上评估关键的X连锁细胞死亡蛋白(X连锁凋亡抑制物(XIAP)和凋亡诱导因子(AIF))，以确定第二X染色体对缺血敏感性的贡献。 与公共健康相关：在过去的五年里，有数据显示，在缺血损伤后激活的基本细胞死亡机制强烈地受到生物性别的影响。性染色体(XX和XY)对中风敏感性的贡献尚不清楚，但可能在一定程度上解释了中风发病率和预后的显著性别差异。我们假设，基于染色体补体，缺血性细胞死亡的基本机制在男性和女性中不同。我们将评估继发于减数分裂不分离的单X染色体(XO)小鼠的卒中结果。39，XO小鼠将与40，XX和40，XY窝产仔进行比较，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.