与HIV相关的神经认知疾病的新机制研究

HIV-1 is most well-known for its devastating effects on the immune system and the resulting AIDS, it can also cause HIV-associated neurocognitive disorders (HAND). Although the introduction of highly active antiretroviral therapy (HAART) has prolonged and improved the lives of infected individuals, it does not provide complete protection against neurological damage in HIV/AIDS. It becomes more important to understand the mechanisms of neurocognitive disorders during HIV-1 infection since the life span of HIV patients is longer. AMPA receptors mediate fast synaptic transmission and play pivotal roles in synaptic plasticity and memory. Our hypothesis is whether AMPA receptors are one of the major players responsible for neurocognitive disorders induced by HIV-1 infection. Previous studies by our lab have established a HIV-1 replication model in astrocytes with IFN priming. We hypothesize that infection of HIV-1 in astrocytes will lead to alteration of AMPA receptor expression, subunit composition, and death of neurons. Techniques including HIV-1 infection with IFN priming model, primary neuronal culture, surface protein labeling, and other molecular and cellular skills will be employed to investigate and support our hypothesis. Results from these proposed studies may lead to the discovery of new mechanisms and new therapeutic targets for prevention and treatment of HAND.

艾滋病病毒除了众所周知的破坏免疫系统和导致艾滋病，它还引发神经认知疾病。高效抗逆转录病毒治疗可以延缓患者的生命，但它并不能彻底治愈艾滋病患者的神经损伤。因此了解艾滋病病毒感染导致神经认知障碍的机制就尤其重要。AMPA受体介导快速突触传递并在突触可塑性和记忆中起关键作用。我们假设AMPA受体在HIV-1感染诱导神经认知疾病中是否是最重要的分子之一。本项目组前期研究建立了用IFN预处理在星型胶质细胞中复制HIV-1的模型，我们提出星型胶质细胞感染HIV-1会影响AMPA受体表达和亚基组成并导致神经元死亡的假说。我们拟用IFN预处理HIV-1感染模型，原代神经元培养，膜蛋白标记，和其它分子生物学与细胞生物学等方法，探索和证明前述假设。该项目的完成对阐明艾滋病病毒感染导致神经认知障碍的机制具有重要意义，为艾滋病引发的神经认知疾病的预防和治疗提供新靶点和思路。

艾滋病病毒可以引发神经认知疾病，因此了解艾滋病病毒感染导致神经认知障碍的机制就尤其重要，AMPA受体在介导快速突触传递中起关键作用。我们假设AMPA受体在HIV-1感染诱导神经认知疾病中是否是最重要的分子之一，星型胶质细胞感染 HIV-1会影响 AMPA 受体表达和亚基组成并导致神经元死亡。我们建立了HIV感染的胶质细胞与神经元共培养的方法, 研究发现胶质细胞感染HIV-1能影响神经元表达AMPAR。我们首次发现HIV可以引起神经细胞凋亡，p53 凋亡刺激蛋白2（Apoptosis Stimulating Protein of p53–2，ASPP2） 在神经细胞凋亡中起着重要作用。该研究对阐明艾滋病病毒感染导致神经认知障碍的机制具有重要意义,为艾滋病引发的神经认知疾病的预防和治疗提供了新靶点和思路。