Gender Susceptibility to Demyelination/Remyelination

描述(由申请人提供)：一些自身免疫性疾病在易感性和严重性方面表现出性别差异。多发性硬化症困扰女性的频率几乎是男性的两倍；然而，男性往往有更严重的疾病概况和死亡率。在我们的小鼠脱髓鞘/重髓鞘形成模型中，我们发现，长期暴露于神经毒性药物铜必利酮的雄性小鼠，在中枢神经系统经历了间歇性的脱髓鞘/重髓鞘形成。在第三次脱髓鞘后，雄性小鼠出现癫痫发作并死亡，而雌性小鼠虽然经历了类似的脱髓鞘/重新髓鞘形成，但存活时间更长。这项建议调查了雌激素、雌激素受体和生长因子在癫痫发作和脱髓鞘疾病中可能解释性别差异的作用。我们将研究雌激素作用的可能机制，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。我们希望了解这些因素的相互作用，并阐明可能改变或改善男女中枢神经系统脱髓鞘疾病的机制。

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.