Contribution of the X Chromosome to Sex Differences in Stroke

项目总结 这项提案的总体目标是确定调节缺血性中风的性染色体基因 目的是研究老年人大脑的敏感性，并探索其潜在的调节作用的机制。一直以来 越来越多的人认识到中风是一种性二型性疾病，然而，潜在的机制 这些性别差异是未知的。老年人是中风患者的大多数，老年人 与年龄匹配的男性相比，女性的发病率、发病率和死亡率都更高， 而这些差异不能仅仅用性腺激素的暴露来解释。以前的工作有 研究表明，性染色体互补对老年动物的中风敏感性有选择性的影响， 当性腺激素在两性之间相等时。我们发现，有一种影响， X染色体剂量(一个X或XX)对小胶质细胞激活和免疫反应的影响。一位杰出的 衰老X染色体的特征是第二条X染色体上基因的遗传沉默 变得不完整，允许基因逃脱X染色体失活(XCI)。这将导致 在许多组织中，这些X逃逸基因在XX细胞和XY细胞中都有较高的表达。Kdm6a和Kdm5c 是两个X逃脱者，可以调节干扰素调节因子(IRF)的表达 负责通过表观遗传修饰激活小胶质细胞。最近的研究发现Kdm6a和Kdm6a Kdm5c在老年女性脑缺血小胶质细胞中的表达高于男性。我们的 中心假说是X染色体互补与老年人的中风敏感性有关 X逃逸基因Kdm6a和Kdm5c在老年人中对IRF1/3/4/5/8进行表观遗传学修饰 小胶质细胞导致性别特异性炎症反应。在目标1中，我们将使用XY*鼠标模型 确定X染色体是否与老年动物的中风敏感性有关。AIM 2将使用 可诱导条件性基因敲除动物模型验证Kdm6a和Kdm5c性别的假说 通过表观遗传修饰机制对中风预后产生具体影响，即 分别标记H3K27me3和H3K4me3去甲基化。目标3将检验X的假设 染色体和Kdm6a/Kdm5c介导调节小胶质细胞活化和免疫应答 IRF1/3/4/5/8表达式。这些拟议的研究将调查Kdm6a/5c- H3K27me3/H3K4me3-IRFS信号轴，一个非常创新和新颖的领域。我们假设这是 通路在导致老年人卒中性别差异中起着关键作用。

PROJECT SUMMARY The overall goal of this proposal is to determine the sex chromosome genes that regulate ischemic stroke sensitivity in the aged brain, and to explore the mechanisms underlying their regulatory role. It has been increasingly recognized that stroke is a sexually dimorphic disease, however, the mechanisms underlying these sex differences are not known. The elderly constitute the majority of stroke victims, and aged women have a higher incidence, higher morbidity and higher mortality compared to age-matched men, and these differences cannot be explained solely by exposure to gonadal hormones. Previous work has shown the sex chromosome complement contributes to stroke sensitivity selectively in aged animals, when gonadal hormones are equivalent between the sexes. We have found that there is an effect of the X chromosome dosage (one X or XX) on microglial activation and immune responses. A prominent feature of the aged X chromosome is that genetic silencing of genes on the second X chromosome becomes incomplete, allowing for genes to escape from X-chromosome inactivation (XCI). This results in higher expression of these X escapee genes in XX vs. XY cells in many tissues. Kdm6a and Kdm5c are two X escapees that can regulate expression of interferon regulatory factors (IRFs) that are responsible for microglial activation through epigenetic modification. Recent work has found Kdm6a and Kdm5c are more highly expressed in microglia derived from aged female vs. male ischemic brain. Our CENTRAL HYPOTHESIS is that X chromosome complement contributes to stroke sensitivity in the aged brain, AND that the X escapee genes Kdm6a and Kdm5c epigenetically modify IRF1/3/4/5/8 in aged microglia leading to sex-specific inflammatory responses. In Aim 1 we will use the XY* mouse model to determine if the X chromosome contributes to stroke sensitivity in aged animals. Aim 2 will use an inducible conditional knock out (ICKO) animal model to test the hypothesis that Kdm6a and Kdm5c sex specifically impact on stroke outcomes through a mechanism of epigenetic modification, i.e. demethylation of H3K27me3 and H3K4me3 marks respectively. Aim 3 will test the hypothesis that X chromosome and Kdm6a/Kdm5c regulate microglial activation and immune responses through mediation of IRF1/3/4/5/8 expression. These proposed studies will investigate the Kdm6a/5c- H3k27me3/H3K4me3-IRFs signaling axes, a very innovative and novel area. We hypothesize that this pathway plays a critical role in inducing sex differences in stroke in the aged.