Sex differences in the CNS during disease

疾病期间中枢神经系统的性别差异

• 批准号: 7962439
• 负责人: RHONDA R VOSKUHL
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7962439
• 关键词: Biological Models; Bone Marrow; Brain; Cells; Central Nervous System Diseases; Cerebellum; Chimera organism; Clinical; Complement; Development; Disease; Disease model; Dose; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Exposure to; Female; Genes; Gonadal Steroid Hormones; Grant; Hematopoietic System; Immune; Immune response; Immune system; Infiltration; Inflammatory; Investigation; Modeling; Multiple Sclerosis; Mus; Neuraxis; Outcome; Ovary; Pathogenesis; Peripheral; Ploidies; Public Health; Role; SJL Mouse; Severities; Sex Characteristics; Sex Chromosomes; Spinal Cord; System; Y Chromosome; dosage; male; nervous system disorder; neuropathology; public health relevance; reconstitution; response; response to injury; sry Genes

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.

描述（由申请人提供）：许多神经系统疾病都具有性别差异的特征。神经病理学通常包括免疫细胞的浸润，这种免疫浸润可能导致疾病发病机制。由于众所周知，免疫系统中存在性别差异，这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。通过改变具有共同免疫系统的宿主体内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反应中的作用。我们将使用所有中枢神经系统疾病模型中炎症性最强的一种——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。我们将使用性染色体互补（XX 与 XY）不同但性腺类型相同的小鼠来确定性染色体的影响，而不存在暴露于不同类型性激素的混杂影响。具体来说，在目标 1 中，我们将确定 XX 小鼠与 XY 小鼠相比更严重的 EAE 是否是由于中枢神经系统中的性染色体效应所致。在目标 #2 中，我们将确定 EAE 期间 CNS 中性染色体的影响是否是由于 X 或 Y 基因的剂量所致。最后，在目标 #3 中，我们将使用性腺类型不同（雌性与雄性）但具有相同性染色体补体（XX 与 XX Sry）的小鼠来确定雌性 EAE 是否比雄性更严重，小鼠的中枢神经系统是由于性激素的作用所致。 公共健康相关性：这是一项探索性 (R21) 拨款，旨在使用多发性硬化症模型（实验性自身免疫性脑脊髓炎）确定性染色体和性激素对中枢神经系统对免疫攻击的反应的影响。该提案将建立一个模型系统，以确定性染色体和性激素对多种以性别差异为特征的神经系统疾病的影响。