Gender Susceptibility to Demyelination/Remyelination

脱髓鞘/髓鞘再生的性别易感性

• 批准号: 6612477
• 负责人: GLENN K. MATSUSHIMA
• 金额: $ 32.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612477
• 关键词: astrocytes; cell differentiation; convulsions; disease /disorder model; estradiol; estrogen receptors; estrogens; gender difference; genetically modified animals; hormone regulation /control mechanism; insulinlike growth factor; interleukin 1; laboratory mouse; macrophage; microglia; multiple sclerosis; myelination; myelinopathy; neurotoxins; oligodendroglia; pathologic process; receptor expression

DESCRIPTION (provided by applicant): A number of autoimmune diseases show gender differences in susceptibility and severity. Multiple Sclerosis afflicts females at nearly twice the frequency as males; however, males tend to have a more severe disease profile and mortality. In our murine model of demyelination/remyelination that show features similar to MS, we find male mice that are chronically exposed to a neurointoxicant, cuprizone, undergo episodic demyelination/remyelination in the central nervous system. After a third episode of demyelination, male mice show grand mal seizures and die whereas females, although undergo similar episodic demyelination/remyelination, remain viable longer. This proposal investigates the role of estrogen, estrogen receptors and growth factors that may account for gender differences in seizures and demyelinating disease. We will study a plausible mechanism for the action of estrogen, test in vivo whether estrogen and IGF-1 can alter disease progression in male and female mice, and the role of estrogen receptors in gender differences. Our hope is to understand the interplay of these factors and elucidate mechanisms that may alter or ameliorate CNS demyelinating disease in both genders.

描述（由申请人提供）：许多自身免疫性疾病在易感性和严重性方面存在性别差异。多发性硬化症折磨女性的频率几乎是男性的两倍;然而，男性往往具有更严重的疾病特征和死亡率。在我们的脱髓鞘/髓鞘再生的小鼠模型中，显示出与MS相似的特征，我们发现长期暴露于神经毒性剂铜腙的雄性小鼠在中枢神经系统中经历了间歇性脱髓鞘/髓鞘再生。在第三次脱髓鞘发作后，雄性小鼠显示癫痫大发作并死亡，而雌性小鼠虽然经历类似的发作性脱髓鞘/髓鞘再生，但存活时间更长。这项提案调查雌激素，雌激素受体和生长因子的作用，可能占癫痫发作和脱髓鞘疾病的性别差异。我们将研究雌激素作用的合理机制，在体内测试雌激素和IGF-1是否可以改变雄性和雌性小鼠的疾病进展，以及雌激素受体在性别差异中的作用。我们的希望是了解这些因素的相互作用，并阐明可能改变或改善两种性别的中枢神经系统脱髓鞘疾病的机制。