GPLD1: Association with Cognition and Amelioration through Exercise in Aging People with HIV

摘要 该应用将研究磷脂酰肌醇-聚糖特异性磷脂酶 D 的新作用 （GPLD1）与体力活动（PA）、认知结果和相关中介途径有关，包括 老年艾滋病毒感染者 (PWH) 的炎症、凝血、线粒体指数和血管重塑。 尽管 PA 可以促进 HIV 患者更好的认知功能和生活质量，但 PA 对许多老龄 PWH 来说是个问题 由于神经病、心肺疾病和其他疾病造成的身体限制。全身性GPLD1 最近被证明可以概括运动对神经源性和认知的益处，并可能代表 为那些身体有缺陷的人提供锻炼神经益处的另一种方法。在现有队列中 100 名 PWH（50 名参与 PA 干预和 50 名对照）中，我们将量化 GPLD1 水平如何变化 PA 干预前后以及这些水平如何与血浆炎症标志物相关， 凝血、血管重塑、线粒体指数和神经认知（NC）表现。我们建议病患休养生息 Fitbit 记录的 PA 水平越高，加速度计监测将显示出更大的增加 GPLD1比PA低。我们假设基线时较高的 GPLD1 将与改善相关 炎症标志物、异常凝血、线粒体指数和血管重塑以及更大的 PA 干预期间 GPLD1 的增加将与这些指数的较大改善相关。 此外，我们预计更高的基线 GPLD1 将与更好的 NC 性能相关联，并且 GPLD1 6 个月 PA 干预期间的增加将与改善 NC 表现相关。除了人类 研究中，我们将进行转化工作来评估 GPLD1 发挥有益作用的机制。 这些将包括在抗逆转录病毒治疗（ART）下病毒抑制的 PWH 动物模型中进行的研究， EcoHIV小鼠模型。在这些动物中，我们将测量 GPLD1 给药对认知和能力的影响。 炎症和凝血标志物，包括评估 GPLD1 的有益作用是否被某种物质阻断 抑制剂（磷脂酸）。此外，我们还将描述炎症、线粒体指数和 GPLD1 处理小鼠脑组织中突触树突的完整性。我们期望对 EcoHIV 小鼠进行 GPLD1 治疗 将改善行为表现，减少脑组织炎症并改善突触树突完整性 和线粒体指数。为了未来的一期临床试验，我们将检查 GPLD1 对肝脏的影响 对小鼠的毒性。我们还将评估神经元培养物中 GPLD1 对线粒体生物合成的影响，以及 通过在 PA 干预中将培养物暴露于人类血浆中来进行神经发生。我们预计 PWH 血浆 与较低的 PA 相比，较高的 PA 将刺激海马线粒体生物发生和神经发生，并且 将确定血清 GPLD1 是否与这些结果相关。检查 GPLD1 对 PWH 的影响，我们的 转化设计，以及将先前的工作扩展到 GPLD1 的脑机制，包括炎症和 线粒体功能因抗逆转录病毒治疗（ART）相关的神经毒性而受损，但它是创新的。

SUMMARY This application will study a novel role of the enzyme phosphatidylinositol-glycan-specific phospholipase D (GPLD1) in relation to physical activity (PA), cognitive outcomes, and relevant mediating pathways, including inflammation, coagulation, mitochondrial indices and vascular remodeling in aging people with HIV (PWH). Although PA promotes better cognitive function and quality of life in HIV, PA is problematic for many aging PWH due to physical limitations from neuropathy, cardiopulmonary disease, and other conditions. Systemic GPLD1 was recently shown to recapitulate the neurogenic and cognitive benefits of exercise and may represent an alternative approach to gain neural benefits of exercise for those with physical limitations. In an existing cohort of 100 PWH (50 participating in a PA intervention and 50 controls), we will quantify how GPLD1 levels change before and after the PA intervention and how these levels associate with plasma markers of inflammation, clotting, vascular remodeling, mitochondrial indices and neurocognitive (NC) performance. We propose PWH with higher levels of PA documented by Fitbit and accelerometer monitoring will show greater increases in GPLD1 than those with lower PA. We hypothesize that higher GPLD1 at baseline will associate with improved markers of inflammation, abnormal clotting, mitochondrial indices and vascular remodeling and that greater increases in GPLD1 during the PA intervention will correlate with larger improvements in these indices. Additionally, we expect that higher baseline GPLD1 will associate with better NC performance and that GPLD1 increases during the 6-month PA intervention will associate with improving NC performance. In addition to human studies, we will perform translational work to evaluate mechanisms by which GPLD1 exerts salutary effects. These will include studies in an animal model of virally suppressed PWH on antiretroviral therapy (ART), the EcoHIV mouse model. In these animals, we will measure the effects of GPLD1 administration on cognition and markers of inflammation and clotting, including evaluating if the beneficial effects of GPLD1 are blocked by an inhibitor (phosphatidic acid). In addition, we will characterize inflammation, mitochondrial indices and synaptodendritic integrity in brain tissue from GPLD1-treated mice. We expect GPLD1 treatment in EcoHIV mice will improve behavioral performance, reduce brain tissue inflammation and improve synaptodendritic integrity and mitochondrial indices. In service of future Phase 1 clinical trials, we will examine GPLD1 effects on liver toxicity in mice. We will also evaluate neuronal cultures for GPLD1 effects on mitochondrial biogenesis and neurogenesis by exposing cultures to plasma from humans in the PA intervention. We expect PWH plasma with higher PA will stimulate hippocampal mitochondrial biogenesis and neurogenesis compared to lower PA, and will determine if serum GPLD1 associates with these outcomes. Examining GPLD1 effects in PWH, our translational design, and extension of prior works into brain mechanisms of GPLD1, including inflammation and mitochondrial function, which is impaired by antiretroviral therapy (ART)-related neurotoxicity, are innovative.