Inflammation and delayed cognitive dysfunction after stroke

描述（由申请人提供）：高达30%的中风患者在中风后的几个月和几年内经历认知能力下降。这种痴呆通常被称为血管性痴呆，其病因尚不清楚。我们的目标是开发卒中后痴呆的第一个模型，以改进其分类，确定病因并开发治疗方法。我们开发了一种新的中风模型，它产生了高度一致的皮层损伤。在中风后的第一周，老鼠有运动和感觉缺陷，但没有认知缺陷。在接下来的几周里，他们从感觉和运动缺陷中恢复过来，然而，他们经历了认知能力的下降，再现了人类血管性痴呆的一种类型。我们发现认知缺陷的发展与中风小鼠纹状体和内囊延迟炎症反应的出现有关，其特征是活化的巨噬细胞/小胶质细胞和T细胞的浸润。我们假设这种炎症反应是对中风病变轴突的沃勒氏变性的反应。此外，我们假设，由于中枢神经系统的沃勒氏变性非常缓慢，需要数月至数年才能消退，这种炎症可能导致T细胞介导的自身免疫，这可能是导致大量中风患者痴呆的原因。为了验证这一假设，我们建议在我们的小鼠模型中确定认知障碍的结构基础，确定认知障碍是否与自身免疫相关，并确定T细胞是否是认知功能障碍发生的必要条件。我们还将确定多次中风是否会加速和增强对中风的免疫反应，以及对大脑抗原的耐受性是否可以预防认知功能障碍。为了帮助我实现这些目标，我向专家导师和顾问寻求帮助，在我需要进一步培训的每个领域提供指导。在我的导师Buckwalter博士、共同导师Wyss-Coray博士的帮助下，以及我的顾问Longo博士、Steinman博士和Shamloo博士的帮助下，我将获得广泛的实验技术和分析方法方面的专业知识。我还制定了一个培训计划，以促进我向终身学术职位的过渡，其中包括学习管理、指导和求职技能。我的长期目标是开发血管性痴呆的治疗方法，以改善患者及其护理人员的生活。拟议的研究和培训计划将对实现这一目标作出巨大贡献。

DESCRIPTION (provided by applicant): 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.