APOLIPOPROTEIN E EFFECT ON THE CNS IMMUNE RESPONSE

载脂蛋白E（apoE）是一种由299个氨基酸组成的蛋白质，具有多种生物学活性。 生物学特性，包括在胆固醇运输中的作用， 免疫调节，以及在神经损伤和修复中的假定作用。 最近的证据表明，三种常见的apoE亚型之一， E4与患阿尔茨海默病的风险增加有关 （散发性和迟发性家族性），以及各种 包括闭合性头部损伤 颅内出血和脑缺血。 我们将测试 apoE是CNS生物学相关介质的假设 对急性和慢性损伤的反应。 我们还将检验假设 在这些免疫调节基因中存在同种型特异性差异， 功能协调发展的 我们的初步证据表明apoE抑制了 神经胶质细胞介导的内源性炎症反应，也可能 当血脑屏障被破坏时， 暴露了 我们还证明了apoE调节CNS 反应局灶性缺血在体内，我们的初步观察是 这与这些效应是同种型特异性的可能性一致。 我们建议描述apoE在调节中枢神经系统中的作用， 利用apoE缺陷小鼠的炎症反应和小鼠 表达人E2、E3和E4转基因以制备细胞培养物 模型和CNS损伤和炎症的体内模型。这 监督的研究经验将与先进的教学相结合 免疫学和神经生物学的课程 后半叶 在此期间，我们将研究apoE影响 免疫反应。 具体来说，我们将重点关注受体相互作用和调节， 信号转导途径在此期间，重点将放在 发展更复杂的研究技能，以促进独立性。 总之，这项建议将研究apoE在调节 中枢神经系统的免疫反应，并将提供基本的训练， 免疫学和神经生物学是发展和独立 神经免疫学的研究生涯

Apolipopoprotein E (apoE) is a 299 amino acid protein with multiple biological properties, including a role in cholesterol trafficking, immumomodulation, and a putative role in nerve injury and repair. Recent evidence suggests that the one of the three common apoE isoforms, E4 is associated with increased risk for developing Alzheimer's disease (sporadic and late onset familial), and poor prognosis after a variety of acute neurological insults, including closed head injury, intracranial, hemorrhage, and cerebral ischemia. We will test the hypothesis that apoE is a biologically relevant mediator of the CNS response to acute and chronic injury. We will also test the hypothesis that there are isoform-specific differences in these immunoregulatory functions. Our preliminary evidence suggests that apoE suppresses the endogenous inflammatory response mediated by glial cells, and may also inhibit the cellular immune response when the blood-brain barrier is compromised. We have also demonstrated that apoE modulates the CNS reaction to focal ischemia in vivo, and our preliminary observations are consistent with the possibility that these effects are isoform-specific. We propose to characterize the role of apoE in modulating the CNS inflammatory response by utilizing apoE deficient mice and mice expressing the human E2, E3, and E4 transgenes to prepare cell culture models and in vivo models of CNS injury and inflammation. This supervised research experience will be integrated with advanced didactic coursework in immunology and neurobiology. In the latter part of the grant period, we will examine the molecular basis by which apoE affects the immune response. Specifically, we will focus on receptor interactions and modulation of signal transduction pathways. During this period, the focus will be on developing more sophisticated research skill to facilitate independence. In summary, this proposal will examine the role of apoE in modulating the CNS immune response and will provide the fundamental training in immunology and neurobiology necessary for developing and independent research career in neuroimmunology.