IGF induced neuronal protection and HIV-1 infection

IGF 诱导神经元保护和 HIV-1 感染

• 批准号: 6672686
• 负责人: Krzysztof Reiss
• 金额: $ 26.93万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672686
• 关键词: AIDS /HIV neuropathy; HIV infections; biological signal transduction; cytoprotection; growth factor receptors; insulinlike growth factor; nerve injury; neuroprotectants; tissue /cell culture; tumor necrosis factor alpha

Disorders of the central nervous system (CNS), including dementia, are common complications of HIV infection. Although the advent of HAART therapy initially decreased morbidity and mortality due to HIV infection, including CNS abnormalities, the incidence of CNS disease has increased in recent years. This increase may in part represent the diminishing effectiveness of HAART therapy due to the prevalence of resistant strains as well as the relatively poor distribution of anti-virals in the CNS compartment. The current increase in HIV -induced neurological disorders as co-morbid conditions in HIV infection suggests the importance of developing additional strategies for the treatment and/or prevention of viral induced injury to the CNS. The studies proposed here focus on a major pathway promoting neuro-protection, the insulin-like growth factor I (IGF-I). Several lines of evidence suggest that this protective pathway is impaired in HlV infection, presumably leaving neuronal cells, as well as other cell types, vulnerable to the pro-apoptotic effects of induced cytokines and toxic metabolites. In our preliminary studies we demonstrate the ability of the IGF-I system to counteract the deleterious effects of TNF-alpha on the survival of differentiated neurons. We further show that the IGF-I receptor (IGF-IR) is activated in patients with HIV associated dementia (HAD) as determined by immunohistochemical analysis of tissue specimens with antibody specific for the phosphorylated (active) form of the receptor. The studies proposed here will test the hypothesis that the cross-talk between the IGF-IR and TNF-alpha receptor signaling pathways is important in determining the extent of neuronal injury in the context of HIV infection. We will examine this hypothesis in the context of two Specific Aims. In the first Specific Aim we will identify the threshold level of IGF-I receptor necessary for neuro-protection, and the receptor signaling domaids required for this effect. In the second Specific Aim, we will examine the interplay between the IGF-I and TNF-alpha signaling pathways and the specific signaling molecules responsible for IGF-I mediated neuro-protection. It is anticipated that the studies performed within the context of this application will contribute to the development of a novel therapeutic strategy based on the utilization and/or mobilization of the IGF-I signaling pathway.

包括痴呆症在内的中枢神经系统(CNS)疾病是艾滋病毒感染的常见并发症。尽管HAART疗法的出现最初降低了HIV感染的发病率和死亡率，包括中枢神经系统异常，但近年来中枢神经系统疾病的发病率有所上升。这一增加可能在一定程度上表明，由于耐药菌株的流行以及抗病毒药物在中枢神经系统中的相对较差分布，HAART治疗的有效性正在减弱。目前，艾滋病毒引起的神经系统疾病作为艾滋病毒感染的共病情况的增加表明，发展更多的 治疗和/或预防病毒引起的中枢神经系统损伤的策略。这里提出的研究重点是促进神经保护的主要途径，胰岛素样生长因子I(IGF-I)。一些证据表明，在HLV感染中，这一保护途径受到损害，可能使神经元细胞以及其他类型的细胞容易受到诱导细胞因子和有毒代谢物的促凋亡作用。在我们的初步研究中，我们证明了IGF-I系统能够抵消肿瘤坏死因子-α的有害影响。 关于分化的神经元的存活。我们进一步证明，IGF-I受体(IGF-IR)在HIV相关性痴呆(HAD)患者中被激活，这是通过对具有针对该受体的磷酸化(活性)形式的抗体的组织标本的免疫组织化学分析确定的。本文提出的研究将检验这一假设，即IGF-IR和TNF-α受体信号通路之间的相互作用在确定HIV感染背景下神经元损伤的程度方面是重要的。我们将在两个具体目标的背景下检验这一假设。在第一个特定目标中，我们将确定IGF-I受体的阈值 对神经保护是必需的，而这种作用所需的受体信号转导域。在第二个具体目标中，我们将研究IGF-I和TNF-α信号通路与负责IGF-I介导的神经保护的特定信号分子之间的相互作用。预计在本申请范围内进行的研究将有助于开发基于IGF-I信号通路的利用和/或动员的新的治疗策略。