Sex differences in the CNS during disease

描述（由申请人提供）：许多神经系统疾病的特征是性别差异。神经病理常包括免疫细胞的浸润，这种免疫浸润可能参与疾病的发病机制。由于已知免疫系统存在性别差异，这就使对中枢神经系统性别差异的研究变得混乱。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。通过在具有共同免疫系统的宿主中改变性染色体或性激素，可以确定性染色体和性激素在脑损伤反应中的作用。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系统疾病的适用性。我们将使用具有相同性腺类型的性染色体补体不同的小鼠（XX vs. XY），以确定在没有暴露于不同类型性激素的混淆效应的情况下性染色体的影响。具体来说，在目标1中，我们将确定XX小鼠EAE的严重程度是否高于XY小鼠，这是由于中枢神经系统中的性染色体作用。在目标#2中，我们将确定EAE期间中枢神经系统中的性染色体效应是由于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，雌性与雄性，同时具有相同的性染色体补体（XX vs. XX Sry），以确定雌性EAE比雄性小鼠更严重是否是由于中枢神经系统中的性激素作用。

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.