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

摘要 这一应用将研究磷脂酰肌醇-葡聚糖特异性磷脂酶D的新作用 (GPLD1)与体力活动(PA)、认知结果和相关的中介途径有关，包括 老年HIV(PWH)患者的炎症、凝血、线粒体指标和血管重构。 尽管PA促进了HIV患者更好的认知功能和生活质量，但PA对许多老化的PWH来说是个问题 由于神经病、心肺疾病和其他条件的身体限制。系统性GPLD1 最近被证明概括了锻炼的神经源性和认知益处，并可能代表着一种 对于身体有缺陷的人来说，获得锻炼的神经益处的另一种方法。在现有的队列中 在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，以及这些水平与血浆炎症标志物的关系， 凝血、血管重塑、线粒体指数和神经认知(NC)表现。我们建议威尔斯亲王医院 随着Fitbit和加速度计监测记录的PA水平较高， GPLD1值明显低于PA值低的患者。我们假设基准线上较高的GPLD1将与改善相关联 炎症、凝血异常、线粒体指数和血管重构的标志物以及更大的 在PA干预期间，GPLD1的增加将与这些指数的更大改善相关。 此外，我们预计更高的基准GPLD1将与更好的NC性能相关联，并且GPLD1 在6个月的PA干预期间，增加将与NC性能的改善相关。除了人类 在这项研究中，我们将进行翻译工作，以评估GPLD1发挥有益作用的机制。 这些将包括在病毒抑制的PWH动物模型上进行的抗逆转录病毒治疗(ART)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 炎症和凝血的标志物，包括评估GPLD1的益处是否被一种 抑制剂(磷脂酸)。此外，我们还将描述炎症、线粒体指数和 GPLD1处理的小鼠脑组织中突触树突的完整性。我们期待GPLD1在EcoHIV小鼠中的治疗 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。在未来的第一阶段临床试验中，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对线粒体生物发生和GPLD1的影响。 在PA干预中，将培养物暴露于来自人类的血浆中进行神经再生。我们预计PWH等离子体与 与低PA相比，高PA可刺激海马区线粒体的生物发生和神经发生 将确定血清GPLD1是否与这些结果相关。研究威尔斯亲王医院的GPLD1效应，我们的 翻译设计，并将以前的工作扩展到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，这是创新的。

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.