ApoE-mimetic peptides protect against brain injury

描述(由申请人提供)： 载脂蛋白E(ApoE)是一种由299个氨基酸组成的蛋白质，具有多种生物学特性。除了在胆固醇代谢中的明确作用外，载脂蛋白E似乎在人类神经系统疾病中扮演着特别重要的角色。特别是，apoE4是该蛋白的三种常见人类亚型之一，与晚发性家族性和散发性阿尔茨海默病的发病率增加以及多发性硬化症、颅内出血和中风患者的不良神经预后有关。最近，也有一些独立的观察发现，闭合性脑损伤后载脂蛋白E亚型与功能预后之间存在强烈的相关性。 在这项建议中，我们将利用表达不同人类载脂蛋白E亚型的靶向替换小鼠来鉴定载脂蛋白E在我们最近表征的小鼠脑损伤模型中的异构体特异性作用。虽然这个模型使用急性死亡率、小脑和运动缺陷作为短期终点，但我们也将模拟神经认知功能障碍，这是创伤性脑损伤常见的临床长期后果。我们将专门测试这一假设，即内源性apoE的表达通过以同型特异性的方式调节神经胶质细胞的激活和中枢神经系统的炎症反应来改变短期和长期的创伤后神经功能障碍。接下来，我们将继续我们的工作，证明源自apoE受体结合区的小肽可以在体内发挥神经保护作用，并可能作为一种新的治疗策略来降低与创伤性脑损伤相关的急性死亡率和长期神经认知障碍。我们将使用这个系统来研究靶向替换小鼠中治疗性载脂蛋白E多肽和人源化载脂蛋白E背景之间可能的药物基因组相互作用。

DESCRIPTION (provided by applicant): Apolipoprotein E (apoE) is a 299 amino acid protein with multiple biological properties. In addition to its well defined role in cholesterol metabolism, apoE appears to play a singularly important role in human neurological disease. In particular, apoE4, one of the three common human isoforms of this protein, has been associated with increased incidence of developing late-onset familial and sporadic Alzheimer's Disease, and poor neurological outcome in patients with multiple sclerosis, intracranial hemorrhage, and stroke. Recently, there have also been a number of independent observations identifying a robust association between apoE isoform and functional outcome following closed head injury. In this proposal, we will utilize targeted replacement mice expressing the different human apoE isoforms to identify the isoform-specific role of apoE in a murine head injury model that we have recently characterized. Although this model utilizes acute mortality, cerebellar and motor deficits as short-term endpoints, we will also model the neurocognitive dysfunction that is a common clinical long-term consequence of traumatic brain injury. We will specifically test the hypothesis that the endogenous expression of apoE modifies short-term and long-term post-traumatic neurological deficits by modulating glial activation and the CNS inflammatory response in an isoform-specific manner. We will next extend our work demonstrating that small peptides derived from the receptor-binding region of apoE can exert neuroprotective effects in vivo, and may serve as a novel therapeutic strategy to reduce the acute mortality and long term neurocognitive deficits associated with traumatic brain injury. We will use this system to investigate possible pharmacogenomic interactions between the therapeutic apoE peptide and the humanized apoE background in the targeted replacement mice.