Treatment of chronic traumatic encephalopathy in a mouse model with a side effect free erythropoietin derived immune modulator.

用无副作用的促红细胞生成素衍生的免疫调节剂治疗小鼠模型中的慢性创伤性脑病。

• 批准号: 9816582
• 负责人: PETER C DOWLING
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816582
• 关键词: Affect; Alzheimer' s disease model; Animal Disease Models; Animal Model; Anxiety; Area; Astrocytes; Behavioral; Behavioral Symptoms; Brain Concussion; Chronic; Clinical; Dangerousness; Data; Degenerative Disorder; Dementia; Deterioration; Development; Disease; Disease Progression; Disease model; Emotional; Erythrocytes; Erythropoietin; Experimental Autoimmune Encephalomyelitis; Experimental Models; Explosion; Exposure to; Head; Hematopoiesis; Human; Immune; Immunohistochemistry; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Laboratory mice; Lead; Literature; Memory; Memory Loss; Mild Concussions; Military Personnel; Modeling; Moods; Motor; Mus; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Patients; Peptide Fragments; Peptides; Process; Publishing; Rehabilitation Research; Reporting; Research; Research Personnel; Soldier; Sports; Suicide; Symptoms; Tauopathies; Testing; Veterans; Work; axon injury; base; cerebral atrophy; chronic traumatic encephalopathy; clinically relevant; cranium; cytokine; experimental study; mouse model; neuroinflammation; neuropathology; novel; novel therapeutics; preclinical trial; programs; response; side effect; treatment effect

This project seeks to examine a treatment for chronic traumatic encephalopathy (CTE). CTE is a degenerative disease that afflicts individuals who have received multiple concussive injuries such as soldiers or players of professional contact sports. It is often marked by progressive neurological deterioration. The disease may lead to memory loss, mood problems, suicidality and dementia and there is presently no known cure. Neuropathologically the disease is associated with chronic neuroinflammation, axonal injury, brain atrophy and tauopathy. There is extensive evidence that long term inflammation worsens neurodegenerative diseases, and specifically tauopathies. This study examines the hypothesis that downregulating this inflammation will slow or arrest the progression of CTE. The proposal employs JM4, a novel immune/inflammatory regulatory agent, to control neuroinflammation. JM4 is a short peptide derived from the cytokine erythropoietin. Whole molecule erythropoietin has well established neuroprotective and immune/inflammatory modulating effects. However, its use in clinical settings is limited since it can lead to dangerous polycythemic levels of red blood cells. JM4 is a short peptide fragment of erythropoietin that retains the cytokine's beneficial effects without the side effect of hematopoiesis. Preliminary studies show that it is highly effective in reducing the immune inflammatory responses in several models of experimental autoimmune encephalomyelitis. Furthermore, in a mouse model of Alzheimer's disease it reduces clinical signs, microglial and astrocytic activation and tauopathy. Preliminary data in a mouse model of CTE indicates that it decreases the associated memory and anxiety deficits. The proposed studies will examine the ability of JM4 to treat CTE using the following experiments: 1) Establishing a model of CTE. Since there is presently no generally accepted animal model of CTE we will appraise two closed cranium models that have been reported in the literature. The first employs multiple direct impacts to the head of experimental mice over a 1 week period. The second model exposes the mice to blast like loading by placing them in the path of a simulated explosion. Both models have been reported to produce chronic neuroinflammation, tauopathy and behavioral deficits. Mice will be followed using tests of anxiety, memory and motor ability. After 6 months, mice will be sacrificed to study neuroinflammation, proinflammatory cytokines and tauopathy using immunohistochemistry. 2) Examining the effect of JM4 in the treatment of CTE. The optimum model from experiment 1 will be selected and the efficacy of JM4 will be tested. Mice will be exposed to the selected injury and then treated with JM4 for 10 consecutive days, either immediately following the injury, or after a 1 month delay (to simulate the effect of delaying treatment until behavioral deficits become apparent). Mice will be examined using the same behavioral and immunohistochemical tests employed above. We anticipate that treatment of the mice with JM4 will reduce inflammation and decrease or eliminate both the behavioral and neuropathological signs of CTE. If successful this will be the first potential treatment developed for this disease.

该项目旨在研究慢性创伤性脑病（CTE）的治疗方法。 CTE 是一种退行性疾病，患者遭受过多次脑震荡 士兵或职业接触运动运动员等受伤。它常常被标记为 进行性神经功能恶化。该疾病可能导致记忆丧失、情绪问题、 自杀和痴呆，目前尚无已知的治疗方法。神经病理学上的疾病 与慢性神经炎症、轴突损伤、脑萎缩和 tau 蛋白病有关。 有大量证据表明长期炎症会加剧神经退行性病变 疾病，特别是tau蛋白病。这项研究检验了下调的假设 这种炎症会减缓或阻止 CTE 的进展。该提案采用了JM4，一种新颖的 免疫/炎症调节剂，控制神经炎症。 JM4是一种短肽 源自细胞因子促红细胞生成素。全分子促红细胞生成素已得到很好的证实 神经保护和免疫/炎症调节作用。但其在临床上的应用 设置受到限制，因为它可能导致红细胞危险的红细胞增多水平。 JM4是一个 促红细胞生成素的短肽片段，保留了细胞因子的有益作用，而无需 造血的副作用。初步研究表明，它可以非常有效地减少 几种实验性自身免疫模型中的免疫炎症反应 脑脊髓炎。此外，在阿尔茨海默病小鼠模型中，它减少了临床症状 体征、小胶质细胞和星形细胞激活以及 tau 蛋白病。小鼠模型的初步数据 CTE 表明它可以减少相关的记忆和焦虑缺陷。 拟议的研究将使用以下方法检验 JM4 治疗 CTE 的能力 实验： 1）建立CTE模型。由于目前还没有普遍接受的动物 CTE 模型 我们将评估已报道的两个闭合颅骨模型 在文献中。第一个对实验头部进行多次直接撞击 小鼠超过 1 周的时间。第二种模型让小鼠承受类似负载的爆炸 将它们放置在模拟爆炸的路径中。两种型号均已 据报道会产生慢性神经炎症、tau蛋白病和行为缺陷。 将通过焦虑、记忆和运动能力测试来跟踪小鼠。 6后 几个月后，小鼠将被处死以研究神经炎症、促炎症 使用免疫组织化学检测细胞因子和 tau 蛋白病。 2)检验JM4治疗CTE的效果。最优模型由 选择实验1来测试JM4的功效。老鼠将会 暴露于选定的损伤，然后连续10天接受JM4治疗， 受伤后立即或延迟 1 个月后（以模拟效果） 延迟治疗直至行为缺陷变得明显）。老鼠将会 使用相同的行为和免疫组织化学测试进行检查 多于。 我们预计用 JM4 治疗小鼠将减少炎症并减少 或消除 CTE 的行为和神经病理学症状。如果成功的话这将是 针对这种疾病开发的第一个潜在治疗方法。