Sex differences in the CNS during disease

描述(申请人提供)：许多神经系统疾病的特点是性别差异。神经病理通常包括免疫细胞的渗透，这种免疫渗透可能导致疾病的发生。由于已知免疫系统中存在性别差异，这就混淆了对中枢神经系统性别差异的研究。因此，我们将使用骨髓嵌合体来研究中枢神经系统的性别差异。通过改变由共同免疫系统重组的宿主中的性染色体或性激素，人们可以确定性染色体和性激素在大脑对损伤的反应中所起的作用。我们将使用所有中枢神经系统疾病模型中最具炎症性的模型之一，多发性硬化症模型，实验性自身免疫性脑脊髓炎(EAE)，来展示这种方法对各种神经疾病的适用性。我们将使用性腺类型相同但性染色体组成不同的小鼠(XX和XY)来确定在没有暴露于不同类型的性激素的混杂影响的情况下，性染色体的影响。具体地说，在目标1中，我们将确定XX小鼠与XY-小鼠相比，EAE的严重程度是否归因于中枢神经系统中的性染色体效应。在目标2中，我们将确定EAE期间中枢神经系统的性染色体效应是否源于X或Y基因的剂量。最后，在目标#3中，我们将使用性腺类型不同的小鼠，雌性和雄性，但具有相同的性染色体组成(XX和XX Sry)，以确定与雄性相比，雌性小鼠EAE的严重程度是否归因于中枢神经系统中的性激素效应。 公共卫生相关性：这是一项探索性(R21)拨款，旨在确定性染色体和性激素对中枢神经系统对多发性硬化症模型-实验性自身免疫性脑脊髓炎-免疫攻击的反应的影响。这项提案将建立一个模型系统，以确定性染色体和性激素对各种以性别差异为特征的神经疾病的影响。

DESCRIPTION (provided by applicant): Numerous neurological diseases are characterized by a sex difference. The neuropathology often includes infiltration of immune cells, with this immune infiltration potentially contributing to disease pathogenesis. Since it is known that sex differences exist in the immune system, this confounds investigations into sex differences in the CNS. Thus, we will use bone marrow chimeras to investigate sex differences in the CNS. By varying sex chromosomes or sex hormones in hosts reconstituted with a common immune system, one can ascertain the role of sex chromosomes and sex hormones on the brain response to injury. We will use one of the most inflammatory of all CNS disease models, the multiple sclerosis model, experimental autoimmune encephalomyelitis (EAE), to show applicability of this approach to a variety of neurological diseases. We will employ mice which differ in the complement of sex chromosomes (XX vs. XY), while having the same gonadal type, to determine the effect of sex chromosomes in the absence of confounding effects of exposure to different types of sex hormones. Specifically, in aim #1 we will determine whether the greater severity of EAE in XX, as compared to XY-, mice is due to sex chromosome effects in the CNS. In aim #2, we will determine if the sex chromosome effect in the CNS during EAE is due to the dose of X or Y genes. Finally in aim #3, we will use mice which differ in gonadal type, female vs. male, while having the same sex chromosome complement (XX vs. XX Sry) to determine whether the greater severity of EAE in female, as compared to male, mice is due to sex hormone effects in the CNS. PUBLIC HEALTH RELEVANCE: This is an exploratory (R21) grant to determine the effect of sex chromosomes and sex hormones on the central nervous system's response to an immune attack using the multiple sclerosis model, experimental autoimmune encephalomyelitis. This proposal will establish a model system to determine the effect of sex chromosomes and sex hormones on a variety of neurological diseases characterized by a sex difference.