Mechanisms of sex differences in blood-brain barrier biology

 描述(申请人提供)：这项建议是我的实验室的一个新方向，即确定多发性硬化症易感性的性别差异的发育起源 (毫秒)。MS是一种自身免疫性中枢神经系统(CNS)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是女性最常见的疾病形式，是一种新的神经功能障碍(复发)的反复发作被临床稳定(缓解)期分开的情况。SJL小鼠品系是检测多发性硬化症性别差异的标准模型，因为它在雌性动物的易感性和RREAE方面表现出类似的性别偏见。在已发表的研究中，我们发现SJL小鼠中枢神经系统(CNS)血管系统中神经鞘氨醇1-磷酸受体2(S1PR2)表达的固有性别差异通过破坏黏附连接来调节内皮细胞的极性，并有助于与男性相比女性疾病周期的发展。目前还不清楚正常性分化的过程如何在调节血脑屏障(BBB)稳定性的途径中活动。在这项提案中，我们将利用S1PR2表达的性别差异来开发揭示BBB生物学中调节性别差异的分子机制的方法。因为有证据表明雌激素的急性效应与RRMS和S1PR2表达的性别差异无关，所以这项建议的重点是性染色体补充的作用和性激素对血脑屏障S1PR2表达的性别差异的组织效应。我们假设S1PR2内皮细胞表达的性别差异是通过发生在发育过程中的组织效应来实现的。我们进一步假设，染色质调节通过改变参与血脑屏障功能的基因的表达来建立额外的性别特异性效应。在这个提案中，我们将：1)确定S1PR2表达的性别差异是否通过细胞固有的内皮细胞基因表达的改变而发生；2)确定性别染色体补充和/或性激素的组织效应是否导致BMEC S1PR2表达的性别差异。我们的发现将定义性二态基因表达和血脑屏障功能之间的新接口，并可能确定以性别特异性方式治疗多发性硬化症患者疾病的新策略。

 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.