Apolipoprotein E effect on the CNS immune response

载脂蛋白E （apoE）是一种含有299个氨基酸的蛋白质，具有多种生物学特性，包括胆固醇转运、免疫调节以及神经损伤和修复。最近的证据表明，三种常见apoE亚型之一的E4与阿尔茨海默病（散发性和晚发性家族性）发生风险增加以及各种急性神经损伤（包括闭合性脑损伤、颅内出血和脑缺血）后预后不良相关。我们还将测试这些免疫调节功能存在同种异构体特异性差异的假设。我们的初步证据表明，apoE抑制由神经胶质细胞介导的内源性炎症反应，并可能在血脑屏障受损时抑制细胞免疫反应。我们还证明，apoE调节中枢神经系统对体内局灶性缺血的反应，我们的初步观察结果与这些作用具有同型特异性的可能性一致。我们建议利用apoE缺陷小鼠和表达人E2、E3和E4转基因的小鼠制备细胞培养模型和体内CNS损伤和炎症模型，表征apoE在调节CNS炎症反应中的作用。这种有监督的研究经验将与免疫学和神经生物学的高级教学课程相结合。在资助期的后半部分，我们将研究载脂蛋白e影响免疫反应的分子基础。具体而言，我们将重点关注受体相互作用和信号转导途径的调节。在此期间，重点将放在发展更复杂的研究，以促进独立。综上所述，本提案将研究apoE在调节中枢神经系统免疫反应中的作用，并将为神经免疫学的发展和独立研究事业提供必要的免疫学和神经生物学基础培训。

Apolipoprotein E (apoE) is a 299 amino acid protein with multiple biological properties, including a role in cholesterol trafficking, immunomodulation, 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 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 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.