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Mechanism of Inflammatory Related Brain Dysfunction after Spinal Cord Injury

脊髓损伤后炎症相关脑功能障碍的机制

基本信息

批准号：
10597985
负责人：
ALAN Ira FADEN
金额：
$ 42.67万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597985
关键词：
Ablation Address Adult Affect Agreement Alzheimer&apos s Disease Anti-Inflammatory Agents Antibodies Attenuated Autonomic Dysfunction Axon Basic Science Behavior Brain Brain region CSF1R gene CXCR3 gene Cell Separation Cerebral cortex Chronic Clinical Trials Cognition Cognition Disorders Cognitive Craniocerebral Trauma Cysteine Data Dementia Development Future Genetic Hippocampus ITGAM gene Impaired cognition Impairment In Vitro Inflammation Inflammatory Inflammatory Response Injections Injury Intervention Learning Ligands Link Mediating Memory Mental Depression Messenger RNA Microglia Modeling Molecular Mood Disorders Moods Motor Mus Nerve Degeneration Neuronal Injury Neuropsychological Tests Neuropsychology Patient Self-Report Patients Performance Pharmaceutical Preparations Pilot Projects Quality of life Rattus Recombinant Proteins Recording of previous events Recovery Recovery of Function Rehabilitation therapy Reporting Research Risk Role Spinal Cord Lesions Spinal cord injury Spinal cord injury patients Synapses Testing Thalamic structure Therapeutic Intervention Transgenic Mice Up-Regulation Work antagonist brain dysfunction brain parenchyma brain tissue chemokine cognitive recovery cytokine dementia risk depressive symptoms effective intervention fall risk functional outcomes gene therapy genetic approach glial activation high risk improved in vivo motor disorder neuroinflammation neuronal survival neuropsychiatry novel therapeutics painful neuropathy pharmacologic progressive neurodegeneration receptor spinal cord and brain injury targeted treatment

项目摘要

Project Summary Neuropsychological deficits have been reported after spinal cord injury (SCI) without concurrent head injury; although most such studies reflect patient self-reports, more formal neuropsychological testing has demonstrated performance impairments with an associated high risk of dementia including deficits in learning and memory. On the other hand, patients with dementia, such as that resulting from Alzheimer’s disease (AD), could have higher risk of falls, and therefore increased risk of SCI. Little research has addressed potential mechanisms for such neuropsychiatric changes or their implications for targeted therapy. There is an urgent need for such studies, as posttraumatic dementia such as cognitive and psychiatric changes negatively impact rehabilitation and impair recovery. The purpose of this study is to identify the mechanisms responsible for these less well examined yet important consequences of SCI and test the hypothesis that SCI-triggered release of CCL21 in the brain contributes to spreading neuroinflammation with cognitive dysfunction and depressive-like behavior, which can be improved by targeting specific mechanisms of neuroinflammation. We will use transgenic mice and molecular interventions to delineate the role of CCL21 as a key regulator of brain microglial activation and related down-stream injury mechanisms in SCI. Aim 1 will identify that SCI-induced CCL21 elevation mediates detrimental microglial activation in the brain through NOX2 activity. Multiple quantitative assessments of microglia activation will be combined with a molecular/genetic intervention targeting CCL21 to test the hypothesis that SCI-induced release of CCL21 in key regions of the brain contributes to detrimental microglial activation through NOX2 activity. Aim 2 will demonstrate that genetic depletion or pharmacological inhibition of CCL21/NOX2 reduces detrimental microglial activation, resulting in improved cognitive decline and depressive-like behavior. Complimentary pharmacological, molecular, and genetic approaches will be used to test the hypothesis that brain CCL21/NOX2-mediated inflammation after SCI causes chronic neurodegeneration associated with cognitive decline and depressive-like behavior. Aim 3 will determine that genetic or pharmacological microglial ablation after SCI reduces brain neuroinflammation leading to improved functional recovery. Using genetic or pharmacological microglia-deletion, we will examine the role of resident microglia in SCI-mediated neuroinflammation in the brain and functional outcomes. The information gained from these studies would have an important positive impact by identifying the key mechanisms involved in important yet largely ignored brain changes after SCI and identifying potential therapeutic interventions.

项目总结