Inflammation and delayed cognitive dysfunction after stroke

项目摘要/摘要。高达30%的中风患者在接下来的几个月里认知能力下降 中风之后的几年里。这种痴呆症通常被称为血管性痴呆，其病因是 未知。我们的目标是开发第一个卒中后痴呆模型，以改善其 分类，确定原因(S)，制定治疗方法。我们开发了一种新的中风模型 这会造成高度一致的皮质损伤。在中风后的第一周，小鼠有一个运动和 有感觉缺陷，但没有认知缺陷。在接下来的几周里，他们从感官上恢复过来， 运动障碍，然而，他们经历了认知能力下降，概括了一种类型的血管性痴呆 在人类身上。我们发现，认知缺陷的发展与外表有关 中风小鼠纹状体和内囊迟发性炎症反应的特征 通过激活巨噬细胞/小胶质细胞和T细胞的渗透。我们假设这起煽动性事件 反应是对卒中病变所投射的轴突的沃勒式变性的反应。 此外，我们假设，由于中枢神经系统的沃勒式退化非常缓慢， 在几个月到几年的时间里，这种炎症可能会导致T细胞介导的自身免疫，而这 可能是导致大量中风患者患痴呆症的原因。为了检验这一假设，我们提出了 为了在我们的小鼠模型中确定认知障碍的结构基础，确定认知 损伤与自身免疫相关，并决定T细胞是否是认知所必需的 就会出现功能障碍。我们还将确定多次中风是否会加速和增强免疫力 对中风的反应，以及对大脑抗原的耐受性是否可以预防认知功能障碍。来帮助我 实现这些目标我曾寻求专家导师和顾问的帮助，在以下方面提供指导 我需要进一步培训的每一个领域。在我的导师巴克沃特博士、共同导师博士的帮助下 Wyss-Coray，和我的顾问Longo博士、Steinman博士和Shamloo博士一起，我将获得 在广泛的实验技术和分析方法方面具有专业知识。我还把我的 一项培训计划，帮助我过渡到结合学习的终身教职学术职位 管理、指导和求职技能。我的长期目标是开发治疗血管疾病的方法 痴呆症以改善患者及其照顾者的生活。拟议的研究和培训计划 将为实现这一目标做出巨大贡献。

Project Summary/Abstract. Up to 30% of stroke patients experience cognitive decline in the months and years after stroke. This dementia is commonly referred to as vascular dementia and its etiology is unknown. Our goal has been to develop the first model of post stroke dementia to improve its classification, determine the cause(s) and develop treatments. We developed a new model of stroke that creates a highly consistent cortical lesion. In the first week after stroke mice have a motor and sensory deficit but no cognitive deficit. In the weeks that follow they recover from their sensory and motor deficit, however they experience cognitive decline, recapitulating one type of vascular dementia in humans. We have found that the development of the cognitive deficit correlates with the appearance of a delayed inflammatory response in the striatum and internal capsule of stroked mice, characterized by activated macrophages/microglia and infiltration of T cells. We hypothesize that this inflammatory response is in response to Wallerian degeneration of the axons that project from the stroke lesion. Furthermore we hypothesize that because Wallerian degeneration in the CNS is very slow, taking months to years to resolve, this inflammation may cause T cell mediated autoimmunity, and that this may be the cause of dementia in a large number of stroke patients. To test this hypothesis we propose to determine the structural basis of the cognitive impairment in our mouse model, determine if cognitive impairment correlates with autoimmunity, and determine if T cells are necessary for cognitive dysfunction to occur. We will also determine if multiple strokes accelerate and amplify the immune response to stroke, and if tolerization to brain antigens can prevent cognitive dysfunction. To help me accomplish these aims I have sought help from expert mentors and consultants to provide instruction in each of the areas that I require further training. With the help of my mentor Dr Buckwalter, co-mentor Dr Wyss-Coray, and in conjunction with my consultants Dr Longo, Dr Steinman and Dr Shamloo I will gain expertise in a wide range of experimental techniques and methods of analyses. I have also put together a training plan to facilitate my transition to a tenure-track academic position that incorporates learning management, mentoring and job search skills. My long-term goal is to develop treatments for vascular dementia to improve the lives of patients and their caregivers. The proposed research and training plan will contribute enormously to the accomplishment of this goal.