Neurotrophin Protection in HIV and Aging

描述（由申请人提供）：抗逆转录病毒疗法的引入抑制了全身艾滋病毒负担，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）的渗透能力较差，一个持续的、活跃的病毒库仍然存在，这支持了中枢神经系统疾病的逐渐进展和日益增加的患病率。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障碍。我们预测和预防不良相互作用的能力目前受到对慢性hiv相关免疫激活如何引起神经毒性以及它如何与其他疾病协同作用的不完全理解的限制。树突珠状突起、剪枝和突触丢失是HIV感染、衰老和阿尔茨海默病的常见病理特征。证据支持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的联系。在HIV神经发病机制和衰老的独立研究中，我们已经证明了新的p75神经营养配体LM11A-31可以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神经营养因子受体的神经营养因子信号的改变可能是病理发展的基础。基于这些观察结果，我们假设神经营养因子和钙信号汇聚在HIV和阿尔茨海默病发病机制中共同的调节肌动蛋白细胞骨架和微管相关蛋白的机制上。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。免疫染色和western blot分析肌动蛋白聚合，tau磷酸化，微管相关蛋白磷酸化和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和/或保护的发展。gp120转基因小鼠的正常衰老将被检测，以确定慢性炎症模型对自然衰老的影响，使用胆碱能变性的标准测量以及对微管相关蛋白和突触的更全面的评估。p75神经营养因子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。随后将在衰老的gp120小鼠中测试LM11A-31治疗的效果，时间与病理发展最活跃的时间一致。这些研究将提供与年龄和HIV相关的神经营养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。

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.