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: 8451271
• 负责人: Kristian Paul Doyle
• 金额: $ 8.51万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451271
• 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; 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

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.

描述（由申请人提供）：高达30%的卒中患者在卒中后数月或数年内出现认知功能下降。这种痴呆通常被称为血管性痴呆，其病因尚不清楚。我们的目标是开发第一个中风后痴呆模型，以改善其分类，确定原因并开发治疗方法。我们开发了一种新的中风模型，可以产生高度一致的皮质病变。在中风后的第一周，小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，重现了人类血管性痴呆的一种类型。我们已经发现认知缺陷的发展与中风小鼠纹状体和内囊中延迟的炎症反应的出现相关，其特征在于活化的巨噬细胞/小胶质细胞和T细胞浸润。我们推测，这种炎症反应是对中风病变轴突的沃勒变性的反应。此外，我们假设，由于CNS中的沃勒变性非常缓慢，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所必需的。我们还将确定多次中风是否会加速和放大对中风的免疫反应，以及对脑抗原的耐受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，以帮助我过渡到终身教职的学术职位，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大大有助于实现这一目标。

项目成果

Immunocytochemical localization of (Na+, K+)-ATPase in the goldfish optic nerve.

金鱼视神经中 (Na , K )-ATP 酶的免疫细胞化学定位。

• DOI: 10.1111/j.1471-4159.1981.tb02384.x
• 发表时间: 1981
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Schwartz,M;Ernst,SA;Siegel,GJ;Agranoff,BW
• 通讯作者: Agranoff,BW

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism.

• DOI: 10.1523/eneuro.0076-18.2018
• 发表时间: 2018-09
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Chung AG;Frye JB;Zbesko JC;Constantopoulos E;Hayes M;Figueroa AG;Becktel DA;Antony Day W;Konhilas JP;McKay BS;Nguyen TV;Doyle KP
• 通讯作者: Doyle KP