IGF-1 signaling pathway in HIV-1 in CNS disease

CNS 疾病中 HIV-1 中的 IGF-1 信号通路

• 批准号: 8377379
• 负责人: Krzysztof Reiss
• 金额: $ 29.66万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377379
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Address; Affect; Age; Apoptosis; Area; Astrocytes; Attenuated; Binding; Binding Proteins; Brain; Brain region; Cell Communication; Cell Culture Techniques; Cells; Central Nervous System Diseases; Chemicals; Cleaved cell; Clinical; Cognition Disorders; Collaborations; Computer software; Controlled Environment; Dementia; Disease; Disintegrins; Embryo; Equilibrium; Evaluation; Event; Extracellular Matrix; Failure; Giant Cells; Glial Fibrillary Acidic Protein; HIV; HIV Wasting Syndrome; HIV encephalitis; HIV-1; In Vitro; Infection; Inflammation; Injury; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Integrin Binding; Integrins; Knock-out; Label; Laboratories; Lymphocyte; Maintenance; Mediating; Membrane; Metalloproteases; Microglia; Molecular; Monitor; Nerve Degeneration; Neuraxis; Neuronal Differentiation; Neuronal Injury; Neurons; Nodule; Oligodendroglia; Outcome; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Play; Process; Proteins; Quantitative Evaluations; Role; Sampling; Serine; Severities; Signal Pathway; Signal Transduction; Somatomedins; Somatotropin; Supporting Cell; System; TNF-alpha converting enzyme; Therapeutic; Time; Tissues; Transgenic Model; Transgenic Organisms; Tubulin; Tumor Necrosis Factor-alpha; Tyrosine Phosphorylation; Viral; base; cell type; clinically relevant; density; experience; fluorescence microscope; gray matter; hormone resistance; image reconstruction; in vitro Model; insulin receptor substrate 1 protein; macrophage; nerve stem cell; nervous system disorder; neuron apoptosis; neuron development; neuron loss; neuropathology; neuroprotection; neurotoxicity; notch protein; novel; protein protein interaction; relating to nervous system; release factor; repaired; research study; response; tissue regeneration; white matter

Project #2. IGF-1 signaling pathway in HIV-1 CMS disorders. A significant number of HIV patients develop cognitive disorders and dementia. It is believed that cellular and viral factors released by the HIV-1 infected cells in the white matter, most notably TNFa , are responsible for neuronal injury seen in AIDS brains. Accordingly, we demonstrated that prolonged exposure of differentiated neurons to TNFoc leads to the retraction of neuronal processes in the absence of neuronal apoptosis. HIV-1 infection can also compromise neuroprotective pathways including the insulin-like growth factor 1 (IGF-1) signaling system. Accordingly, in earlier studies we demonstrated that IGF-1 protects neurons from TNFa-induced retraction of neuronal processes. We have demonstrated that TNFa triggers serine phosphorylation of IRS-1 (pS-IRS-1) at the membrane rafts of differentiated neurons, and that pSIRS- 1 interferes with integrin-mediated cellular responses, which are directly involved in the maintenance of neuronal processes and neuronal outgrowth. These observations led us to hypothesize that in HIV encephalitis degeneration of neuronal processes is caused by TNFa-induced interaction between pS-IRS-1 and neuronal integrins, which leads to detachment and retraction of neuronal processes. This detrimental action of TNFoc is counteracted by IGF-l-mediated tyrosine phosphorylation of IRS-1 (pY-IRS-1), which supports the binding of neuronal processes and facilitates tissue remodeling and neuronal outgrowth. We have addressed this hypothesis by experiments described in three Specific Aims. In Aim#1. we will analyze density of neuronal processes in the regions of HIV encephalitis (HIVE) differentially affected by the accumulation of TNFoc. In Aim#2. we will evaluate effects of TNFcc on subcellular localization and phosphorylation status of IRS-1; and will analyze molecular interactions between IRS-1, (31-integrin and ADAMs in primary neuronal cultures from the IGF-IR knockout embryos and from age-matching non-transgenic littermates. Finally, in Aim#3. we will examine effects of IGF-I stimulation on neuronal regeneration and tissue remodeling after TNFa -mediated retraction of neuronal processes in differentiated neurosphere cultures from the IGF-IR knockout embryos and from agematching non-transgenic littermates. The outcome of this project will identify and characterize new molecular events, which affect stability of neuronal processes in the paradigm of HIVE, and possibly other neurological disorders characterized by the accumulation of TNFcc. Understanding the cross interaction between IGF-1 and TNFa signaling pathways will help to develop new IGF-l-based therapeutic approaches against neurological disorders in which retraction/degeneration of neuronal processes is a common event.

项目＃2。 HIV-1 CMS疾病中的IGF-1信号通路。 大量艾滋病毒患者患有认知障碍和痴呆症。据信蜂窝 HIV-1感染细胞在白质中释放的病毒因子，最著名的是TNFA，是负责的 对于在艾滋病大脑中看到的神经元损伤。因此，我们证明了长时间的暴露 在没有神经元的情况下，分化的神经元对TNFOC导致神经元过程的缩回 凋亡。 HIV-1感染还会损害神经保护途径，包括胰岛素样生长 因子1（IGF-1）信号系统。因此，在较早的研究中，我们证明了IGF-1保护 来自TNFA诱导的神经元过程的神经元。我们已经证明了TNFA触发器 IRS-1（PS-IRS-1）在分化神经元的膜筏上的丝氨酸磷酸化，psirs- 1干扰了整联蛋白介导的细胞反应，这些反应直接参与维持 神经元过程和神经元产物。 这些观察结果使我们假设在HIV脑炎中，神经元过程的变性是 由TNFA诱导的PS-IRS-1与神经元整合蛋白之间的相互作用引起的，这导致脱离 和神经元过程的缩回。 TNFOC的这种有害作用被IGF-L介导的 IRS-1（PY-IRS-1）的酪氨酸磷酸化，支持神经元过程的结合 促进组织重塑和神经元的产物。我们已经通过实验解决了这一假设 在三个特定目标中描述。在AIM＃1中。我们将分析神经元过程的密度 HIV脑炎（Hive）受TNFOC积累的差异影响。在AIM＃2中。我们将评估 TNFCC对IRS-1的亚细胞定位和磷酸化状态的影响；并将分析分子 IRS-1（IRS-1的相互作用（31-整合素和ADAMS）来自IGF-IR敲除的原发性神经元培养物中的相互作用 胚胎和年龄匹配的非转基因同窝仔。最后，在AIM＃3中。我们将检查 TNFA介导的回缩后，IGF -1对神经元再生和组织重塑的刺激 来自IGF-IR敲除胚胎的分化神经圈培养物的神经元过程和调和 非转基因同窝。该项目的结果将识别并表征新分子 事件会影响蜂巢范式中神经元过程的稳定性，甚至可能是其他神经系统 以TNFCC积累为特征的疾病。了解IGF-1之间的交叉相互作用 TNFA信号通路将有助于开发针对的新的基于IGF-L的治疗方法 神经元过程的缩回/变性是一个常见事件。