Gp120及其衍生的淀粉样多肽在HIV相关神经认知障碍中的作用及其分子机制

认知障碍等神经系统疾病是影响艾滋病患者生活质量及死亡的重要因素之一。我们前期研究表明，HIV包膜蛋白gp120具有明显神经毒性，机制尚未清楚；gp120在脑内被降解的多肽能自发形成淀粉样纤维并聚集在皮质区。此外，我们发现gp120转基因小鼠及gp120衍生淀粉样多肽诱导神经元细胞CCR5基因表达上调，表明CCR5参与gp120及其淀粉样纤维诱导的神经损伤，拟对CCR5进行功能验证和机制研究，探讨CCR5抑制剂Maraviroc在临床治疗HIV相关神经认知障碍的可能；另外，为探究HIV相关神经认知障碍的分子病因及网络调控机制，本项目拟采用CRISPR/cas9技术对拮抗 gp120神经毒性的相关基因进行全基因组筛选，通过富集差异基因与生信分析，揭示gp120介导HIV神经损伤的高效干预靶点。本项目有望为HIV相关神经认知障碍提供新的的诊断与防治靶标，为寻找新的治疗药物提供新依据。

Neurodegenerative diseases, including cognitive deficits, are a major factor which affects life quality and a major cause of death of AIDS patients. Our previous study showed that gp120 caused neurotoxicity in human neuronal cells. In addition, gp120 could release peptiditic fragment that spontaneously form amyloid fibrils. These gp120 derived amyloid fibrils accumulated in the brain of Tg-GP120 mice. Moreover, We found that CCR5 was involved in the neurocytotoxicity induced by gp120 and its amyloid fibrils. We will perform experiments to study the function and mechanism of CCR5 in GP120-induced neurodegenerative diseases and the potential neuro-protection of maraviroc, a CCR5 antagonist, in vivo. Our study intend to find potential target genes modulating neurotoxicity of GP120 and the related signal pathways, using high-throughput CRISPR/Cas9 genome-wide screening combined with bioinformatics analysis, which might provide a theoretical basis for new antiviral drug targets. Our study will broaden our knowledge in roles of gp120 in neuro-degenerative diseasesand provide potential clinical treatment for HIV-associated neurocognitive disorder.