Neurotrophin Protection in HIV and Aging

神经营养素对艾滋病毒和衰老的保护作用

• 批准号: 8805857
• 负责人: RICK B MEEKER
• 金额: $ 26.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805857
• 关键词: Acceleration; Actins; Address; Age; Aging; Alzheimer' s Disease; Calcium; Calcium Signaling; Central Nervous System Diseases; Chronic; Clinical; Cognition Disorders; Cytoskeleton; Data; Dendrites; Development; Disease; Equilibrium; Exons; Functional disorder; HIV; HIV Envelope Protein gp120; Homeostasis; Human; In Vitro; Individual; Inflammation; Intracellular Transport; Investigation; Investigational Drugs; Knockout Mice; Ligands; Link; Longevity; Macrophage Activation; Measures; Mediating; Mental disorders; Microtubule-Associated Proteins; Mitochondria; Modeling; Mus; NGFR Protein; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Neuropathogenesis; Pathogenesis; Pathology; Pathway interactions; Penetration; Phase; Phosphorylation; Population; Prevalence; Process; Readiness; Regulation; Research Design; Risk; Signal Pathway; Signal Transduction; Stimulus; Synapses; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Transgenic Mice; Translations; Treatment Efficacy; Viral; Virus Diseases; Western Blotting; abeta oligomer; age effect; age related; age related neurodegeneration; antiretroviral therapy; base; cholinergic; cofilin; effective therapy; immune activation; in vivo; in vivo Model; insight; mitochondrial dysfunction; mouse model; neurocognitive disorder; neurotoxicity; neurotrophic factor; normal aging; novel; polymerization; prevent; public health relevance; receptor expression; relating to nervous system; response; standard measure; tau Proteins; tau phosphorylation; transcriptional coactivator p75

DESCRIPTION (provided by applicant): The introduction of antiretroviral therapies that suppress the systemic HIV burden has greatly extended the life span of infected individuals. However, because these compounds have poor penetration into the central nervous system (CNS), a persistent, active viral reservoir remains that supports the gradual progression and increasing prevalence of CNS disease. As the HIV- infected population ages, chronic inflammation is expected to interact adversely with a variety of age-related disease processes that give rise to cognitive and psychiatric disorders. Our ability to predict and prevent adverse interactions is currently limited by an incomplete understanding of how chronic HIV-associated immune activation causes neurotoxicity and how it might synergize with other diseases. Dendritic beading, pruning and synapse loss are common pathological features of HIV infection, aging and Alzheimer disease. Evidence supports an association between this damage and a loss of neurotrophic support as well as a calcium- dependent disruption of actin regulation and intracellular transport. In independent studies of HIV neuropathogenesis and aging we have demonstrated that the novel p75 neurotrophin ligand, LM11A-31, prevents neural dysfunction and damage, in part, by restoring calcium homeostasis. Recent studies of early Alzheimer pathogenesis suggest that alteration in neurotrophin signaling through the p75 neurotrophin receptor may underlie the development of pathology. Based on these observations, we hypothesize that neurotrophin and calcium signaling converge on mechanisms common to HIV and Alzheimer pathogenesis that regulate the actin cytoskeleton and microtubule-associated proteins. The proposed studies will use in vitro and in vivo models of HIV-associated neuropathogenesis in combination with natural neurotrophins (NGF, proNGF), pathogenic molecules associated with aging (Abeta oligomers) and LM11A-31 to define both deleterious and neuroprotective interactions. Immunostaining and western blot analyses of changes in actin polymerization, tau phosphorylation, microtubule associated protein phosphorylation and functional assessments of mitochondrial transport will be used to determine how each challenge contributes to the development of pathology and/or protection. Normal aging in gp120 transgenic mice will be examined to determine the impact of chronic inflammation model on natural aging using standard measures of cholinergic degeneration as well as more global assessments of microtubule-associated proteins and synapses. The contribution of the p75 neurotrophin receptor to pathogenesis will be evaluated in p75 Exon III knockout mice. The efficacy of treatment with LM11A-31 will then be tested in the aging gp120 mice at a time coincident with the most active development of pathology. These studies will provide insights into the cellular dysfunction associated with age- and HIV- associated loss of neurotrophin support and will determine the therapeutic potential of the novel p75 ligand, LM11A-31.

描述（由申请人提供）：抑制全身艾滋病毒负担的抗逆转录病毒疗法的引入大大延长了感染者的寿命。然而，由于这些化合物对中枢神经系统 (CNS) 的渗透性较差，因此仍然存在持续、活跃的病毒库，支持中枢神经系统疾病的逐渐进展和患病率的增加。随着艾滋病毒感染人群的老龄化，慢性炎症预计会与各种与年龄相关的疾病过程产生不利的相互作用，从而导致认知和精神疾病。目前，我们预测和预防不良相互作用的能力受到对慢性艾滋病毒相关免疫激活如何导致神经毒性以及它如何与其他疾病协同作用的不完全了解的限制。树突串珠、修剪和突触丢失是 HIV 感染、衰老和阿尔茨海默病的常见病理特征。有证据表明这种损伤与神经营养支持的丧失以及钙依赖性肌动蛋白调节和细胞内运输的破坏之间存在关联。在 HIV 神经发病机制和衰老的独立研究中，我们证明新型 p75 神经营养蛋白配体 LM11A-31 可以部分通过恢复钙稳态来预防神经功能障碍和损伤。最近对早期阿尔茨海默病发病机制的研究表明，通过 p75 神经营养蛋白受体的神经营养蛋白信号传导的改变可能是病理学发展的基础。基于这些观察，我们假设神经营养蛋白和钙信号传导与艾滋病毒和阿尔茨海默病发病机制中常见的机制一致，调节肌动蛋白细胞骨架和微管相关蛋白。拟议的研究将使用 HIV 相关神经发病机制的体外和体内模型，结合天然神经营养因子（NGF、proNGF）、与衰老相关的致病分子（Abeta 寡聚物）和 LM11A-31 来定义有害和神经保护相互作用。对肌动蛋白聚合、tau 磷酸化、微管相关蛋白磷酸化变化的免疫染色和蛋白质印迹分析以及线粒体运输的功能评估将用于确定每种挑战如何促进病理学和/或保护的发展。将使用胆碱能变性的标准测量以及微管相关蛋白和突触的更全面的评估来检查 gp120 转基因小鼠的正常衰老，以确定慢性炎症模型对自然衰老的影响。 p75 神经营养素受体对发病机制的贡献将在 p75 外显子 III 敲除小鼠中进行评估。然后，在病理学发展最活跃的时间，在衰老的 gp120 小鼠中测试 LM11A-31 治疗的功效。这些研究将深入了解与年龄和 HIV 相关的神经营养素支持丧失相关的细胞功能障碍，并将确定新型 p75 配体 LM11A-31 的治疗潜力。