Platelet Activating Factor, Synaptic Failure & NeuroAIDS

血小板激活因子、突触衰竭

• 批准号: 7162186
• 负责人: HARRIS A GELBARD
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162186
• 关键词: Platelet; Activating; Factor; Synaptic; Failure

DESCRIPTION (provided by applicant): Understanding how HIV-1 wreaks havoc on the CNS despite HAART remains important because people are living long enough to manifest neurologic disease. We assert there is a continuum between normal synaptic function necessary for plasticity and synaptic dysfunction during HIV-1 associated neurologic disease. Between the boundaries of plasticity and pathology, there is a reversible component of synaptic dysfunction that can be ameliorated by HAART or other adjunctive therapies. Therefore, we will investigate morphologic, electrical, and molecular events that underlie this dysfunction. HIV-1 neurotoxins affect convergent cellular pathways that increase synaptic levels of the phospholipid mediator platelet-activating factor (PAF). Although rapidly catabolized, PAF is normally involved in maintaining levels of synaptic glutamate during long term potentiation (LTP), a process that increases the efficacy of synaptic communication and is thought to be the substrate for many cognitive processes indirectly affected by HIV-1, including learning and memory. During HIV-1-induced inflammation, increased synaptic PAF is associated with excitotoxic damage to neurons. Thus we will investigate three hypotheses: (1) Prolonged exposure to PAF can alter the ability of intact synapses to achieve LTP, a measure of synaptic plasticity, by disrupting formation of dendritic spines on post-synaptic neurons either temporarily (protective "beading" response) or permanently ("synaptic apoptosis"). Here we will assess beading in affected dendrites and correlate it with synaptic responses, as well as measure caspase activation, cell viability and confirm specificity of our findings with PAF receptor antagonists. (2) Pathologic exposure to PAF will induce synaptic failure by disruption of normal mitochondrial functions leading to dysregulation of mitochondrial buffering of Ca+2 and production of ATP in stressed synapses. (3) Prolonged exposure to PAF in vivo during excitatory neurotransmission will lead to mitochondrial dysfunction and degeneration of nerve terminals, i.e. synaptic apoptosis. Thus, we will measure changes in synaptic transmission, mitochondrial function, and degeneration of nerve terminals from rodents treated in vivo with PAF. These findings will significantly advance our understanding of how HIV-1 continues to induce neurologic disease despite advances in HAART.

描述（由申请人提供）： 尽管采用 HAART，了解 HIV-1 如何对 CNS 造成严重破坏仍然很重要，因为人们的寿命足以表现出神经系统疾病。我们断言，可塑性所需的正常突触功能与 HIV-1 相关神经系统疾病期间的突触功能障碍之间存在连续性。在可塑性和病理学的界限之间，存在可逆的突触功能障碍，可以通过 HAART 或其他辅助治疗来改善。因此，我们将研究导致这种功能障碍的形态学、电学和分子事件。 HIV-1 神经毒素会影响会聚细胞通路，从而增加磷脂介质血小板激活因子 (PAF) 的突触水平。尽管 PAF 被快速分解代谢，但它通常在长期增强 (LTP) 过程中参与维持突触谷氨酸水平，这是一个提高突触通讯效率的过程，被认为是许多受 HIV-1 间接影响的认知过程的基础，包括学习和记忆。在 HIV-1 诱导的炎症过程中，突触 PAF 的增加与神经元的兴奋性毒性损伤有关。因此，我们将研究三个假设：（1）长时间暴露于 PAF 可以通过暂时破坏突触后神经元上树突棘的形成（保护性“珠状”反应）来改变完整突触实现 LTP（突触可塑性的一种测量）的能力。 ）或永久（“突触凋亡”）。在这里，我们将评估受影响的树突中的珠状现象，并将其与突触反应相关联，并测量 caspase 激活、细胞活力，并确认我们的研究结果与 PAF 受体拮抗剂的特异性。 (2) 病理性暴露于 PAF 会破坏正常线粒体功能，导致应激突触中 Ca+2 线粒体缓冲和 ATP 产生失调，从而诱发突触衰竭。 (3)兴奋性神经传递过程中体内长时间暴露于PAF会导致线粒体功能障碍和神经末梢变性，即突触凋亡。因此，我们将测量体内用 PAF 处理的啮齿动物的突触传递、线粒体功能和神经末梢变性的变化。尽管 HAART 取得了进展，这些发现将显着增进我们对 HIV-1 如何继续诱发神经系统疾病的理解。