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

CNS 疾病中 HIV-1 中的 IGF-1 信号通路

基本信息

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
项目类别：
财政年份：
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

项目摘要

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。大量艾滋病毒患者出现认知障碍和痴呆。据认为，细胞白质中 HIV-1 感染细胞释放的病毒因子，尤其是 TNFa，是造成这种情况的原因。治疗艾滋病大脑中出现的神经元损伤。因此，我们证明，长时间暴露在向 TNFoc 分化的神经元会导致在缺乏神经元的情况下神经元过程的回缩细胞凋亡。 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，在早期的研究中，我们证明 IGF-1 可以保护 TNFa 诱导的神经元突起收缩的神经元。我们已经证明 TNFa 会触发 IRS-1 (pS-IRS-1) 在分化神经元膜筏上的丝氨酸磷酸化，并且 pSIRS- 1 干扰整合素介导的细胞反应，该反应直接参与维持神经元过程和神经元生长。这些观察结果使我们推测，在艾滋病毒脑炎中，神经元过程的退化是由 TNFa 诱导的 pS-IRS-1 和神经元整合素之间的相互作用引起，从而导致脱离和神经元过程的回缩。 TNFα 的这种有害作用可被 IGF-1 介导的物质抵消 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生长。我们通过实验解决了这个假设三个具体目标中进行了描述。目标#1。我们将分析以下区域的神经元过程的密度 HIV 脑炎 (HIVE) 受 TNFα 积累的影响不同。在目标#2 中。我们将评估 TNFcc对IRS-1亚细胞定位和磷酸化状态的影响；并将分析分子在 IGF-IR 敲除的原代神经元培养物中，IRS-1、(31-整合素和 ADAM 之间的相互作用胚胎和来自年龄匹配的非转基因同窝小鼠。最后，在目标#3 中。我们将检查的影响 IGF-I 刺激对 TNFa 介导的神经元再生和组织重塑的影响来自 IGF-IR 敲除胚胎和年龄匹配的分化神经球培养物中的神经元过程非转基因同窝仔猪。该项目的成果将鉴定并表征新分子事件，影响 HIVE 范式中神经元过程的稳定性，并可能影响其他神经系统以 TNFcc 积聚为特征的疾病。了解 IGF-1 之间的交叉相互作用和 TNFa 信号通路将有助于开发新的基于 IGF-l 的治疗方法神经系统疾病，其中神经元过程的回缩/退化是常见事件。