HIV-associated Astrocyte Senescence as a Contributor to NeuroAIDS

HIV相关星形胶质细胞衰老是神经艾滋病的一个促成因素

• 批准号: 9195247
• 负责人: Justin Cohen
• 金额: $ 4.36万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2018-12-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195247
• 关键词: Affect; Age; Age Factors; Age-Years; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Anti-Retroviral Agents; Astrocytes; Brain; Cell Aging; Cell physiology; Cells; Chronic Disease; Coculture Techniques; Complex Mixtures; DNA Damage; Data; Development; Drug Combinations; Elderly; Enzyme-Linked Immunosorbent Assay; Functional disorder; Growth; HIV; HIV Envelope Protein gp120; HIV-1; HIV-associated neurocognitive disorder; Highly Active Antiretroviral Therapy; Homeostasis; Human; Individual; Inflammation; Inflammatory; Inflammatory Response; Intraventricular; Lamivudine; Lead; Longevity; Nerve Degeneration; Neuroglia; Neurologic; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Nucleotides; Oxidative Stress; Oxidative Stress Pathway; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Population; Predisposition; Premature aging syndrome; Proliferating; Proteins; Public Health; Rattus; Reporting; Reverse Transcriptase Inhibitors; Risk; Risk Factors; Ritonavir; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Stimulus; Stress; Telomere Shortening; Therapeutic; Tissues; Toxic effect; United States; Vertebral column; Viral Envelope Proteins; Viral reservoir; Virus; Virus Diseases; abacavir; age related; beta-Galactosidase; biological adaptation to stress; clinically relevant; comorbidity; comparative; cytokine; glial activation; in vivo; inhibitor/antagonist; loss of function; neuroAIDS; neurocognitive disorder; neuroinflammation; neurological pathology; neuron apoptosis; neuropathology; neurotoxicity; paracrine; patient population; premature; programs; response; senescence; telomere

Aging and age related co-morbidities are major risk factors for neurological pathologies. As the population ages, this puts a major strain on public health. One population that is particularly at risk in the United States are human immunodeficiency virus-1 (HIV-1) infected individuals as more than half of the population is now 50 years of age or older. Infected individuals show signs of premature aging and are prone to neurological dysfunctions collectively known as HIV-associated neurocognitive disorders (HAND). The persistence of HAND has been troubling since with the advent of highly active antiretroviral therapy (HAART), the virus is sufficiently suppressed. Possible contributors to HAND therefore include the HAART drugs themselves as well as reservoirs of the gp120 viral envelope protein hidden in the CNS. Since advancing age is critical for HAND, it is likely that there is an interaction between aging and the factors that influence HAND pathology. We propose that an age associated stress response in astrocytes known as cellular senescence in response to HAART drugs and gp120 could be a contributor to HAND. We will examine the senescence-associated DNA damage response, telomere damage and oxidative stress pathways activated in response to these stimuli. Since senescence is accompanied by the secretion of pro-inflammatory proteins known as the senescence- associated secretory phenotype, we will also determine the contribution of senescent astrocytes to inflammation in response to these HIV-associated stimuli. We will also determine which signaling mechanisms contribute to the secretions by using pharmacological inhibitors of major inflammatory centers. Neurons are also sensitive to glial activation and their toxicity in response to activated glia are another possible HAND contributor. We will examine if secretions from HIV-associated senescent astrocyte are able to cause neurotoxicity and whether pharmacological inhibition of inflammation can mitigate this response. Our overall objective is to determine the interaction between aging and HIV-associated factors as a contributor to HAND. Since many age associated pathologies are associated with the accumulation of senescent cells, astrocyte senescence in response to HAART drugs and gp120 could be a major contributor to HAND and Inhibition of this response could be a public health boon as a potential therapy.

衰老和与年龄相关的并存是神经病理的主要危险因素。随着人口的增加 随着年龄的增长，这给公共卫生带来了很大的压力。在美国，一个特别危险的人群 是人类免疫缺陷病毒-1(HIV-1)感染者吗？现在超过一半的人口是50岁 年岁或更大的。感染者表现出过早衰老的迹象，并容易出现神经系统疾病 功能障碍统称为HIV相关神经认知障碍(HAND)。手的执着 自高效抗逆转录病毒疗法(HAART)问世以来一直令人担忧，病毒足以 被压制了。因此，可能的贡献者包括HAART药物本身以及 隐藏在中枢神经系统中的gp120病毒包膜蛋白的储存库。由于年龄增长对手来说至关重要，所以它是 可能在衰老和影响手部病理的因素之间存在交互作用。我们建议 星形胶质细胞的一种与年龄相关的应激反应称为细胞衰老对HAART的反应 药物和gp120可能是手头的贡献者。我们将检查与衰老相关的DNA损伤 对这些刺激的反应、端粒损伤和氧化应激通路被激活。自.以来 衰老伴随着促炎症蛋白的分泌，这种蛋白质被称为衰老- 相关的分泌表型，我们还将确定衰老星形胶质细胞对 炎症是对这些艾滋病毒相关刺激的反应。我们还将确定哪些信令机制 通过使用主要炎症中心的药物抑制剂促进分泌物的分泌。神经元是 另一个可能的因素是对胶质细胞的激活及其毒性反应敏感。 贡献者。我们将检查HIV相关的衰老星形胶质细胞的分泌物是否能够引起 神经毒性以及药物抑制炎症是否可以减轻这种反应。我们的整体 目的是确定老龄化与HIV相关因素之间的交互作用，以作为Hand的贡献者。 由于许多与年龄相关的病理与衰老细胞的积累有关，星形胶质细胞 对HAART药物和gp120的反应中的衰老可能是导致手和抑制的主要因素 作为一种潜在的治疗方法，这种反应可能会对公共健康有利。