C-kit Signaling Pathways Regulate EAE Susceptibility in Male SJL Mice

C-kit 信号通路调节雄性 SJL 小鼠的 EAE 易感性

基本信息

批准号：
8596647
负责人：
Abigail Elizabeth Short
金额：
$ 4.72万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8596647
关键词：
Adoptive Transfer Affect Allergic inflammation Animal Disease Models Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigens Blood - brain barrier anatomy Brain C-KIT Gene CD4 Positive T Lymphocytes Cell Survival Cell physiology Cells Central Nervous System Diseases Characteristics Chronic Data Defect Demyelinations Dendritic Cells Dependence Development Disease Disease Progression Disease susceptibility Environment Ependymal Cell Event Exhibits Experimental Autoimmune Encephalomyelitis Female Genes Genetic Helper-Inducer T-Lymphocyte Hematopoietic Hormonal Hormones Immune Immune response Immunization Incidence Infiltration Inflammation Mediators Inflammatory Ischemic Stroke Laboratories Male Castration Mediating Meninges Modeling Motor Mouse Strains Multiple Sclerosis Mus Myelin Nerve Neuraxis Neurons Paralysed Pathogenesis Pathology Pattern Peptides Peripheral Permeability Phenotype Physiologic pulse Pigments Population Predisposition Prevalence Production Proto-Oncogene Protein c-kit Receptor Protein-Tyrosine Kinases Relapse Reporting Research Rodent Model SJL Mouse Sensory Serum Severities Severity of illness Signal Pathway Signal Transduction Staging Stem Cell Factor T-Cell Development T-Lymphocyte Testing Testosterone Time Tyrosine Variant Woman cell type cellular targeting cytokine disease phenotype disorder subtype functional improvement insight male mast cell melanocyte men mouse model mutant novel patient population public health relevance reconstitution research study response restoration sex sexual dimorphism subcutaneous trafficking

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a debilitating disease of the central nervous system (CNS) characterized by infiltration of autoreactive T lymphocytes and other activated immune cells across the blood brain barrier (BBB) into the CNS. Subsequent nerve demyelination and axonal loss leads to the characteristic decreased motor and sensory functions. In MS, a significant sex dimorphism exists with the prevalence approaching a 3:1 female predominance over males. While genetic, hormonal, and immune response differences have been implicated, the mechanism for this sex dimorphism remains unclear. The animal model of disease, experimental autoimmune encephalomyelitis (EAE), recapitulates many of the features of MS. In SJL mice, the disease presents with ascending paralysis and exhibits a similar female predominance. It has previously been reported that female c-kit mutant (SJL-KitW/W-v ), mast cell deficient mice are less susceptible to relapsing-remitting EAE than their wild type littermates. Further, restoration of mast cell populations to these mice restores a WT-like disease phenotype. Thus, mast cells are important pathogenic contributors to female disease. Surprisingly, in contrast to the less severe disease of female SJL-KitW/W-v mice, male SJL-KitW/W-v mice develop significantly more severe EAE than their WT littermates. These data suggest that either mast cells or other c-kit mediated events are protective in male SJL mice. Several potential mechanisms exist to explain this phenomenon: A) Male mast cells, under the unique hormonal environment, may respond by producing pro-inflammatory mediators in disease. B) Loss of c-kit signaling in DCs could alter the T helper cell response in male mice in disease c) c-kit signals are neuroprotective in males and override the pro-inflammatory effects of c-ckit+ mast cells in EAE. Perhaps most importantly, the disparate phenotypes of the sexes allows for novel insight into the observed sex dimorphism of EAE. We plan to utilize the extensive research completed with female SJL-KitW/W-v mice as a construct to explore male disease. The specific aims of the proposed study are: Aim 1: To identify within what stage of EAE progression c-kit signaling exerts protective in SJL-KitW/W-v male mice. Aim 2: To determine which cell types mediate the c-kit mediated protection in EAE SJL-KitW/W-v male mice.

描述（由申请人提供）：多发性硬化症（MS）是一种使中枢神经系统（CNS）的使人衰弱的疾病，其特征是自身反应性T淋巴细胞浸润和其他激活的免疫细胞跨血脑屏障（BBB）。随后的神经脱髓鞘和轴突损失导致运动和感觉函数的降低。在MS中，存在重大的性二态性，患病率接近男性的女性占主导地位。尽管遗传，激素和免疫反应差异已涉及，但这种性二态性的机制尚不清楚。疾病的动物模型，实验性自身免疫性脑脊髓炎（EAE），概括了MS的许多特征。在SJL小鼠中，该疾病表现出上升的麻痹，并表现出相似的女性占主导地位。以前据报道，雌性C-kit突变体（SJL-KITW/W-V），缺乏肥大细胞的小鼠比其野生型同窝仔不太容易复发EAE。此外，将肥大细胞群恢复到这些小鼠还恢复了WT样疾病表型。因此，肥大细胞是女性疾病的重要致病因素。令人惊讶的是，与雌性SJL-KITW/W-V小鼠的严重疾病较少相反，雄性SJL-KITW/W-V小鼠的表现要比其WT同窝型较为严重。这些数据表明，肥大细胞或其他C-KIT介导的事件在雄性SJL小鼠中具有保护性。有几种潜在的机制来解释这种现象：a）在独特的激素环境下，雄性肥大细胞可能通过产生疾病中的促炎性介体做出反应。 b）DC中C-KIT信号传导的丧失可能会改变疾病中雄性小鼠的T辅助细胞反应C）C-KIT信号在雄性中是神经保护性的，并超出了EAE中C-CKIT+ MAST细胞的促炎作用。也许最重要的是，性别的不同表型可以使人们对观察到的EAE的性二态性进行新颖的了解。我们计划利用雌性SJL-KITW/W-V小鼠完成的广泛研究作为探索男性疾病的一种结构。拟议的研究的具体目的是：目标1：确定在EAE进展阶段C-KIT信号传导在SJL-KITW/W-V雄性小鼠中发挥保护作用。目标2：确定哪种细胞类型介导了EAE SJL-KITW/W-V雄性小鼠中C-Kit介导的保护。