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

总结 本申请将研究磷脂酰肌醇-聚糖特异性磷脂酶D的新作用 （GPLD 1）与体力活动（PA）、认知结果和相关介导途径的关系，包括 炎症，凝血，线粒体指数和血管重塑与艾滋病毒（PWH）的老年人。 虽然PA促进更好的认知功能和艾滋病毒的生活质量，PA是许多老年PWH的问题 由于神经病、心肺疾病和其他疾病的身体限制。系统性GPLD 1 最近被证明概括了运动对神经和认知的好处， 另一种方法，以获得运动对身体限制的神经益处。在现有的队列中， 100例PWH（50例参与PA干预，50例对照），我们将量化GPLD 1水平的变化 在PA干预之前和之后，以及这些水平如何与炎症的血浆标志物相关联， 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 Fitbit记录的PA水平越高，加速计监测将显示 GPLD 1水平低于PA水平者。我们假设基线时较高的GPLD 1与改善的 炎症标志物、异常凝血、线粒体指数和血管重塑， PA干预期间GPLD 1的增加将与这些指标的较大改善相关。 此外，我们预计更高的基线GPLD 1将与更好的NC性能相关，并且GPLD 1 6个月PA干预期间的增加将与改善NC性能相关。除了人类 研究，我们将进行翻译工作，以评估GPLD 1发挥有益作用的机制。 这些研究将包括在病毒抑制的PWH动物模型中进行抗逆转录病毒治疗（ART）的研究， EcoHIV小鼠模型。在这些动物中，我们将测量GPLD 1给药对认知的影响， 炎症和凝血的标志物，包括评估GPLD 1的有益作用是否被一种 抑制剂（磷脂酸）。此外，我们将描述炎症，线粒体指数和 图1示出了来自GPLD 1处理的小鼠的脑组织中的突触树突完整性。我们希望在EcoHIV小鼠中进行GPLD 1治疗 将改善行为表现，减少脑组织炎症，改善突触树突的完整性 和线粒体指数。在未来的1期临床试验中，我们将研究GPLD 1对肝脏的影响， 小鼠毒性。我们还将评估神经元培养物中GPLD 1对线粒体生物发生的影响， 在PA干预中，通过将培养物暴露于来自人类的血浆来促进神经发生。我们希望PWH等离子体 与较低PA相比，较高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GPLD 1是否与这些结果相关。研究PWH中的GPLD 1效应，我们的 翻译设计，并将先前的工作扩展到GPLD 1的大脑机制，包括炎症和 线粒体功能，这是由抗逆转录病毒疗法（ART）相关的神经毒性受损，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.