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

• 批准号: 10380183
• 负责人: ALAN Ira FADEN
• 金额: $ 43.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380183
• 关键词: Ablation; Address; Adult; Affect; Agreement; Alzheimer' s Disease; Anti-Inflammatory Agents; Antibodies; Attenuated; Autonomic Dysfunction; Axon; Basic Science; Behavior; Brain; Brain region; CSF1R gene; CXCR3 gene; Cerebral cortex; Chronic; Clinical Trials; Cognition; Cognition Disorders; Cognitive; Craniocerebral Trauma; Cysteine; Data; Dementia; Development; Future; Genetic; Hippocampus (Brain); 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; Molecular Genetics; Mood Disorders; Moods; Motor; Mus; Nerve Degeneration; Neuronal Injury; Neuropsychological Tests; Neuropsychology; Patient Self-Report; Patients; Performance; Pharmaceutical Preparations; Pharmacology; 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; high risk; improved; in vivo; motor disorder; neuroinflammation; neuronal survival; neuropsychiatry; novel therapeutics; painful neuropathy; progressive neurodegeneration; receptor; spinal cord and brain injury; targeted treatment

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.

项目摘要 已有报道称脊髓损伤(SCI)后出现神经心理障碍，但无合并头部损伤； 尽管大多数这样的研究都反映了患者的自我报告，但更正式的神经心理测试 表现出的表现障碍与痴呆症的相关高风险，包括学习障碍 和记忆。另一方面，痴呆症患者，如阿尔茨海默病(AD)引起的患者， 可能有更高的跌倒风险，因此增加了脊髓损伤的风险。很少有研究涉及到潜在的 这种神经精神变化的机制或其对靶向治疗的影响。有一件急事 需要这样的研究，因为创伤后痴呆症，如认知和精神方面的变化，会产生负面影响 康复和损害康复。这项研究的目的是找出导致 这些不太充分地检验了SCI的重要后果，并检验了SCI触发的假设 CCL21在大脑中的释放有助于传播伴有认知功能障碍的神经炎症和 抑郁样行为，可以通过针对神经炎症的特定机制来改善。 我们将使用转基因小鼠和分子干预来描述CCL21作为关键的作用 脊髓损伤时脑小胶质细胞激活的调节因子及相关的下游损伤机制。目标1将确定 脊髓损伤诱导的CCL21升高介导了脑内有害的小胶质细胞激活 通过NOX2活性。对小胶质细胞激活的多项定量评估将与 针对CCL21的分子/遗传干预验证脊髓损伤诱导的CCL21释放的假说 大脑的关键区域通过NOX2活性促进有害的小胶质细胞激活。目标2将 证明CCL21/NOX2的遗传耗竭或药理抑制可减少 有害的小胶质细胞激活，导致认知功能下降和抑郁样症状的改善 行为。将使用免费的药理学、分子和遗传学方法来测试 脊髓损伤后脑CCL21/NOX2介导炎症导致慢性神经变性的假说 与认知能力下降和类抑郁行为有关。目标3将确定基因或 药物治疗脊髓损伤后小胶质细胞减少导致脑神经炎症 改善了功能恢复。利用遗传或药物上的小胶质细胞缺失，我们将检查 驻留的小胶质细胞在脊髓损伤介导的脑内神经炎症和功能结果中的作用。 从这些研究中获得的信息将通过确定 脊髓损伤后重要但基本被忽视的脑变化的关键机制及其识别潜力 治疗性干预。