Mechanisms of sex differences in blood-brain barrier biology

 描述（由申请人提供）：该建议是我实验室的一个新方向，即确定多发性硬化症易感性性别差异的发育起源 （MS）。MS是一种中枢神经系统（CNS）的自身免疫性脱髓鞘疾病，具有强烈的性别偏见，目前女性与男性的比例接近4：1。复发-缓解型MS RRMS是女性中最常见的疾病形式，是一种新的神经功能障碍的复发发作（复发）被临床稳定期（缓解）隔开的病症。SJL小鼠品系是检查MS性别差异的标准模型，因为其在雌性动物的易感性和RREAE中表现出相似的性别偏倚。在已发表的研究中，我们表明，SJL小鼠中枢神经系统（CNS）血管系统上鞘氨醇1-磷酸受体2（S1 PR 2）表达的细胞内在性别差异通过破坏粘附连接的稳定来调节内皮细胞极性，并有助于女性与男性相比疾病周期的发展。尚未确定的是如何正常的性别分化模式的活动，调节血脑屏障（BBB）的稳定性的途径。在这项提案中，我们将利用S1 PR 2表达的性别差异来开发方法，揭示调节BBB生物学性别差异的分子机制。因为有证据表明，雌激素的急性效应不负责RRMS和S1 PR 2表达的性别差异，该建议的重点是性染色体的作用和组织性激素的影响，在BBB的S1 PR 2表达的性别差异。我们推测，S1 PR 2的内皮细胞表达的性别差异发生通过组织的影响，发生在发展过程中。我们进一步假设，染色质调控通过改变BBB功能相关基因的表达建立了额外的性别特异性效应。在本提案中，我们将：1）确定S1 PR 2表达的性别差异是否通过细胞内在内皮细胞基因表达的改变发生;和2）确定性染色体补体和/或性激素的组织效应是否是BMEC S1 PR 2表达的性别差异的基础。我们的研究结果将定义性二态基因表达和血脑屏障功能之间的新界面，并可能确定新的策略，以性别特异性的方式治疗MS患者的疾病。

 DESCRIPTION (provided by applicant): This proposal is a new direction for my laboratory, which is to define developmental origins of sex differences in susceptibility to multiple sclerosis (MS). MS is an autoimmune, demyelinating disease of the central nervous system (CNS) that has a strong sex bias, with the female to male ratio currently approaching 4:1. Relapsing- remitting MS RRMS, the most common form of the disease in women, is a condition in which recurrent episodes of new neurological dysfunction (relapses) are separated by periods of clinical stability (remission). The SJL strain of mice is a standard model for examining sex differences in MS, as it exhibits a similar sex bias in susceptibility and RREAE in female animals. In published studies we showed that cell intrinsic sex differences in the expression of the sphingosine 1-phosphate receptor 2 (S1PR2) on central nervous system (CNS) vasculature of SJL mice regulates endothelial cell polarity by destabilizing adherens junctions and contributes to the development of disease cycles in females compared with males. Not yet defined is how the process of normal sexual differentiation patterns activity in pathways that regulate blood-brain barrier (BBB) stability. In this proposal we will use sex differences in S1PR2 expression to develop approaches that will uncover molecular mechanisms that regulate sex differences in BBB biology. Because evidence suggests that acute effects of estrogens are not responsible for sex differences in RRMS and in S1PR2 expression, the focus of this proposal is the role of sex chromosome complement and the organizational effects of sex hormones on sex differences in S1PR2 expression at the BBB. We hypothesize that sex differences in endothelial cell expression of S1PR2 occur via organizational effects that occur during development. We further hypothesize that chromatin regulation establishes additional sex-specific effects through altered expression of genes involved in BBB function. In this proposal we will: 1) Determine whether sex-differences in S1PR2 expression occur via cell intrinsic endothelial cell alterations in gene expression; and 2) Determine whether sex chromosome complement and/or organizational effects of sex hormones underlie sex differences in BMEC S1PR2 expression. Our findings will define new interfaces between sexually dimorphic gene expression and BBB function, and may identify new strategies to treat disease in MS patients in a sex-specific fashion.