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: 8826622
• 负责人: Kristian Paul Doyle
• 金额: $ 19.04万
• 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/8826622
• 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; 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; motor recovery; 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.

项目总结/抽象。多达30%的中风患者在这几个月里会出现认知能力下降