Mechanisms of sex differences in blood-brain barrier biology

血脑屏障生物学中性别差异的机制

基本信息

批准号：
9204440
负责人：
Robyn S Klein
金额：
$ 22.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204440
关键词：
Acute Adherens Junction Affect Androgens Animals Autoimmune Process Biology Birth Blood - brain barrier anatomy CNS autoimmunity Cell Polarity Cells Cerebellum Chromatin Clinical Clinical Trials Data Demyelinating Diseases Development Disease Disease remission Endothelial Cells Estradiol Estrogens Evaluation Exhibits Experimental Autoimmune Encephalomyelitis Exposure to Female Gene Dosage Gene Expression Genes Genetic Genotype Gonadal Hormones Gonadal Steroid Hormones Human Immune response In Vitro Laboratories MicroRNAs Modeling Molecular Molecular Profiling Mouse Strains Multiple Sclerosis Mus Neonatal Neuraxis Neurologic Dysfunctions Ovariectomy Pathway interactions Pattern Ploidies Predisposition Process Proteins Publishing Recurrence Regulation Relapse Relapsing-Remitting Multiple Sclerosis Reporter Role SJL Mouse Sex Bias Sex Characteristics Sex Chromatin Sex Chromosomes Sphingosine-1-Phosphate Receptor Spinal Cord T cell regulation T-Lymphocyte Testing Transgenic Mice Transgenic Organisms Woman X Chromosome Y Chromosome brain endothelial cell cytokine experimental study in vivo male multiple sclerosis patient promoter public health relevance response sex sexual dimorphism transcription factor

项目摘要

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.

描述（由应用程序提供）：此提案是我的实验室的新方向，即定义性别差异的发育起源（多发性硬化症）。 MS是一种具有强烈的性偏见的中枢神经系统（CNS）的自身免疫性，脱髓鞘疾病，目前女性与男性比例接近4：1。复发 - 使MS RRMS是女性最常见的疾病形式，是一种疾病，在这种情况下，新神经功能障碍（复发）的复发性发作通过临床稳定性（缓解）分开。小鼠的SJL菌株是检查MS中性别差异的标准模型，因为它在易感性和雌性动物中表现出相似的性别偏见。在发表的研究中，我们表明，中枢神经系统（S1PR2）在中枢神经系统（CNS）SJL小鼠表达中的细胞固有性别差异，SJL小鼠的脉管系统可通过破坏依赖粘附剂的连接来调节内皮细胞极性，并导致与雌性雌性相比的疾病环境的发展。尚未定义的是如何在调节血脑屏障（BBB）稳定性的途径中进行正常性分化模式活动的过程。在此提案中，我们将使用S1PR2表达中的性别差异来开发可以发现调节BBB生物学性别差异的分子机制的方法。由于证据表明雌激素的急性影响对RRMS的性别差异和S1PR2表达不负责，因此该提案的重点是性染色体完成的作用，以及性恐怖对BBB中S1PR2表达性别差异的组织影响。我们假设S1PR2的内皮细胞表达中的性别差异是通过发展过程中发生的组织效应而发生的。我们进一步假设染色质调节通过改变参与BBB功能的基因的表达来建立额外的性别特异性效应。在此提案中，我们将：1）确定S1PR2表达中的性别差异是否是通过基因表达中固有的内皮细胞改变发生的； 2）确定性染色体的完成和/或性恐怖的组织影响是否是BMEC S1PR2表达中性别差异的基础。我们的发现将定义性二态基因表达和BBB功能之间的新界面，并可以确定以性别特定方式治疗MS患者疾病的新策略。