CONSEQUENCES OF NEF EXPRESSION ON CNS PATHOLOGY

NEF 表达对 CNS 病理学的影响

• 批准号: 6687703
• 负责人: Nora E Sarvetnick
• 金额: $ 37.04万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-20 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687703
• 关键词: AIDS /HIV neuropathy; RNase protection assay; chemokine; enzyme linked immunosorbent assay; genetically modified animals; human immunodeficiency virus; laboratory mouse; microglia; microorganism immunology; monocyte; myelocyte; neuroimmunomodulation; neuropathology; regulatory gene; virulence; virus genetics

HIV infected individuals suffer from debilitating effects of the virus in the central nervous system often leading to dementia. The mechanism by which the virus induces these effects if not fully understood. In the central nervous system, the main reservoir of the virus appears to be the myelomonocytic cells comprised of macrophages and microglia. Recent fascinating research has focused on the pathogenic potential of the HIV NEF gene product. This protein has immense potential to alter the function of differentiated cells by interacting with a number of critical cellular mediators. The overall goal of this project is to further our understanding of the mechanism by which HIV causes central nervous system dysfunction. We will test the hypothesis that the NEF gene product alters the functional specificity of CNS myelomonocytic cells. We have derived a model where the expression of NEF has been targeting to the myelomonocytic compartment of transgenic mice. We will use these mice to define the functional distinctions between NEF expressing microglia and normal microglia. We will test the hypothesis that the expression of NEF alters the activation state and functional properties of microglia causing perturbations to the central nervous system function. We will define alterations in the functional properties of microglia by testing their ability to present antigen, their ability to act as targets for cytotoxic T cells and assess their capacity for proliferation and survival. Finally we will determine the impact of NEF on the ability to mount an immune response to a central nervous system pathogen, integrating what we have learned in the all of the studies, to understand the net impact of myelomonocytic-localized NEF. These studies will illuminate the mechanism whereby NEF, present in myelmonocytic cells contributes to central nervous system dysfunction associated with HIV infection.

感染HIV的个体会受到 病毒在中枢神经系统中的作用常常导致痴呆。的机制 如果不完全了解病毒是如何诱导这些效应的。中部 神经系统，病毒的主要储存库似乎是 由巨噬细胞和小胶质细胞组成的骨髓单核细胞。最近的迷人 研究集中在HIV NEF基因产物的致病潜力上。 这种蛋白质具有巨大的潜力，可以改变分化的 通过与许多关键的细胞介质相互作用来调节细胞。整体 这个项目的目标是进一步了解我们的机制， 艾滋病毒会导致中枢神经系统功能障碍。我们将检验这个假设， NEF基因产物改变CNS骨髓单核细胞的功能特异性， 细胞我们已经推导出一个模型，其中NEF的表达已经靶向 转基因小鼠的骨髓单核细胞区室。我们将用这些老鼠 明确表达NEF的小胶质细胞和正常小胶质细胞之间的功能区别 小胶质细胞我们将检验NEF的表达改变了 引起扰动的小胶质细胞的激活状态和功能特性 对中枢神经系统功能的影响我们将定义更改 通过测试小神经胶质细胞呈递抗原的能力， 它们作为细胞毒性T细胞靶点的能力， for proliferation增殖and survival生存.最后，我们将确定NEF对 对中枢神经系统病原体产生免疫反应的能力， 整合我们在所有研究中学到的知识， 髓单核细胞定位NEF的净影响。这些研究将阐明 存在于髓单核细胞中的NEF有助于中枢神经系统的机制 与HIV感染相关的神经系统功能障碍。