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: 8525780
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525780
• 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; Neurocognitive; 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; 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）：抑制系统性艾滋病毒负担的抗逆转录病毒疗法的引入大大延长了受感染者的寿命。但是，由于这些化合物渗透到中枢神经系统（CNS）中，因此仍然存在持续的活跃病毒储层，可支持CNS疾病的逐渐发展和增加的患病率。随着艾滋病毒感染的人群年龄，慢性炎症有望与各种与年龄相关的疾病过程不利，这会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HIV相关的免疫激活如何引起神经毒性以及如何与其他疾病协同作用的不完全理解的限制。树突状珠子，修剪和突触丧失是艾滋病毒感染，衰老和阿尔茨海默氏病的常见病理特征。证据支持这种损害与神经营养支持的丧失以及依赖性肌动蛋白调节和细胞内转运之间的关联。在HIV神经病发生和衰老的独立研究中，我们已经证明了新型的P75神经营养蛋白配体LM11A-31，通过恢复钙稳态来阻止神经功能障碍和损害。关于阿尔茨海默氏早期发病机理的最新研究表明，神经营养蛋白通过p75神经营养受体的改变可能是病理发展的基础。基于这些观察结果，我们假设神经营养蛋白和钙信号传导在调节肌动蛋白细胞骨架和微管相关蛋白的HIV和阿尔茨海默氏病发病机理上融合。拟议的研究将使用与天然神经营养蛋白（NGF，PRONGF）结合使用HIV相关神经病发生的体外和体内模型，与衰老（ABETA低聚物）和LM11A-31相关的致病分子，以定义有害和神经促性性相互作用。肌动蛋白聚合，TAU磷酸化，微管相关的蛋白质磷酸化和线粒体转运的功能评估的免疫染色和蛋白质印迹分析将用于确定每个挑战如何有助于病理学和/或保护的发展。将检查GP120转基因小鼠的正常老化，以确定慢性炎症模型对胆碱能变性的标准测量以及对微管相关蛋白和突触的全球评估的影响。 p75外显子III基因敲除小鼠将评估p75神经营养蛋白受体对发病机理的贡献。然后，LM11A-31治疗的功效将在衰老的GP120小鼠中与最活跃的病理发展相吻合。这些研究将提供有关与年龄和HIV相关的神经营养蛋白支持丧失相关的细胞功能障碍的见解，并将确定新型p75配体LM11A-31的治疗潜力。