Gender Susceptibility to Demyelination/Remyelination

9)首席研究员/项目主任（最后、第一、中间）：Matsushima， Glenn K描述：说明申请的广泛、长期目标和具体目的，并参考项目与健康的关系。简要描述为实现这些目标的研究设计和方法。避免总结过去的成就和使用第一人称。当与应用程序分离时，此摘要旨在作为对所建议工作的简洁而准确的描述。如果申请获得资助，此描述将成为公开信息，因此，不包括专有/机密信息，请勿超过所提供的空间。许多自身免疫性疾病在易感性和严重程度上表现出性别差异。多发性硬化症折磨女性的频率几乎是男性的两倍；然而，男性往往有更严重的疾病概况和死亡率。在我们的小鼠脱髓鞘/髓鞘再生模型中，显示出与MS相似的特征，我们发现，长期暴露于神经毒物铜酮的雄性小鼠，在中枢神经系统中会出现间歇性脱髓鞘/髓鞘再生。在第三次脱髓鞘发作后，雄性小鼠出现大癫痫发作并死亡，而雌性小鼠虽然经历了类似的脱髓鞘/再脱髓鞘发作，但存活时间更长。本研究探讨了雌激素、雌激素受体和生长因子在癫痫发作和脱髓鞘疾病中可能造成的性别差异。我们将研究雌激素的作用机制，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。网站性能 ======================================== 节结束 ===========================================

9) Principal Investigator/Program Director (Last, first, middle): Matsushima, Glenn K DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information, Therefore, do not include propdetary/confidential information, DO NOT EXCEED TIlE SPACE PROVIDED. A number of autoimmune diseases show gender differences in susceptibility and severity. Multiple scleros s 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. PERFORMANCE SiTE ========================================Section End===========================================