Inflammation and delayed cognitive dysfunction after stroke

中风后炎症和迟发性认知功能障碍

• 批准号: 8779803
• 负责人: Kristian Paul Doyle
• 金额: $ 24.65万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-25 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779803
• 关键词: Affect; American; Animal Model; Animals; Antigens; Appearance; Area; Autoimmune Process; Autoimmune Responses; Autoimmunity; Axon; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Caregivers; Chronic; Classification; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Dementia; Dendritic Spines; Development; Diagnosis; Etiology; Functional disorder; Goals; Hippocampus (Brain); Human; Immune response; Immune system; Impaired cognition; Infiltration; Inflammation; Inflammatory Response; Instruction; Internal Capsule; Label; Lead; Learning; Lesion; Mediating; Memory; Memory Loss; Memory impairment; Mentors; Methods; Microglia; Modeling; Motor; Mus; Names; Nerve Degeneration; Neurites; Neurons; Occupations; Patients; Peripheral; Phenotype; Positioning Attribute; Recovery; Research Personnel; Research Training; Sensory; Stroke; T cell response; T-Lymphocyte; Techniques; Testing; Time; Training; Transgenic Mice; United States; Vascular Dementia; Wallerian Degeneration; abstracting; base; cognitive function; cytokine; experience; help-seeking behavior; high risk; improved; macrophage; motor deficit; mouse model; neuron loss; post stroke; prevent; response; role model; skills; therapy development; white matter

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.

项目摘要/摘要。高达 30% 的中风患者在数月内出现认知能力下降 以及中风​​后数年。这种痴呆通常称为血管性痴呆，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 这会产生高度一致的皮质损伤。中风后第一周，小鼠具有运动能力 感觉缺陷但无认知缺陷。在接下来的几周里，他们从感觉和 运动缺陷，但他们会经历认知能力下降，概括一种类型的血管性痴呆 在人类中。我们发现认知缺陷的发展与外表相关 中风小鼠纹状体和内囊延迟炎症反应的特征 通过活化的巨噬细胞/小胶质细胞和 T 细胞的浸润。我们推测这种炎症 该反应是对从中风病变突出的轴突的华勒变性的反应。 此外，我们假设由于中枢神经系统的华勒变性非常缓慢，因此 数月至数年才能消退，这种炎症可能会导致 T 细胞介导的自身免疫，并且这 可能是导致大量中风患者痴呆的原因。为了检验这个假设，我们提出 为了确定我们的小鼠模型中认知障碍的结构基础，确定认知是否 损伤与自身免疫相关，并确定 T 细胞是否是认知所必需的 发生功能障碍。我们还将确定多次中风是否会加速和增强免疫 对中风的反应，以及对脑抗原的耐受是否可以预防认知功能障碍。来帮助我 为了实现这些目标，我向专家导师和顾问寻求帮助，以提供指导 我需要进一步培训的每个领域。在我的导师巴克沃尔特博士的帮助下，共同导师博士 Wyss-Coray，并与我的顾问 Longo 博士、Steinman 博士和 Shamloo 博士一起，我将获得 广泛的实验技术和分析方法的专业知识。我也整理过 一个培训计划，以促进我过渡到包含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血管治疗方法 痴呆症，以改善患者及其护理人员的生活。拟议的研究和培训计划 将为实现这一目标作出巨大贡献。