Inflammation and delayed cognitive dysfunction after stroke

项目概要/摘要。多达30%的中风患者在数月内出现认知能力下降 以及中风后的几年。这种痴呆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中风后痴呆模型，以改善其 分类，确定原因并制定治疗方法。我们开发了一种新的中风模型 造成了高度一致的皮层损伤在中风后的第一周，小鼠有一个运动， 感官缺陷，但无认知缺陷。在接下来的几周里，他们从感官和精神上恢复过来， 运动缺陷，但他们经历认知能力下降，重演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的延迟炎症反应， 通过活化的巨噬细胞/小胶质细胞和T细胞的浸润。我们假设这种炎症 这种响应是响应于从中风病变突出的轴突的沃勒变性。 此外，我们假设，由于中枢神经系统的沃勒变性非常缓慢， 这种炎症可能会导致T细胞介导的自身免疫， 可能是导致大量中风患者痴呆的原因。为了验证这一假设，我们提出 为了确定我们小鼠模型中认知障碍的结构基础， 损伤与自身免疫相关，并确定T细胞是否是认知所必需的。 功能障碍发生。我们还将确定多次中风是否会加速和放大免疫系统， 如果对脑抗原的耐受可以预防认知功能障碍，帮我 为了实现这些目标，我向专家导师和顾问寻求帮助， 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和我的共同导师 Wyss-Coray，以及我的顾问Longo博士，Steinman博士和Shamloo博士，我将获得 在广泛的实验技术和分析方法的专业知识。我还收集了 一个培训计划，以促进我过渡到一个终身制的学术职位，包括学习 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.