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.

中枢神经系统 (CNS) 疾病，包括痴呆，是 HIV 感染的常见并发症。尽管HAART疗法的出现最初降低了HIV感染（包括中枢神经系统异常）导致的发病率和死亡率，但近年来中枢神经系统疾病的发病率有所增加。这种增加可能部分代表了由于耐药菌株的流行以及中枢神经系统中抗病毒药物的分布相对较差而导致HAART治疗的有效性下降。目前，HIV 引起的神经系统疾病作为 HIV 感染的共病状况有所增加，这表明开发额外的药物的重要性 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关注促进神经保护的主要途径，即胰岛素样生长因子 I (IGF-I)。多项证据表明，这种保护途径在艾滋病毒感染中受到损害，可能使神经元细胞以及其他细胞类型容易受到诱导细胞因子和有毒代谢物的促凋亡作用的影响。在我们的初步研究中，我们证明了 IGF-I 系统抵消 TNF-α 有害作用的能力 影响分化神经元的存活。我们进一步表明，IGF-I 受体 (IGF-IR) 在 HIV 相关痴呆 (HAD) 患者中被激活，这是通过使用针对受体磷酸化（活性）形式的特异性抗体对组织样本进行免疫组织化学分析来确定的。这里提出的研究将检验以下假设：IGF-IR 和 TNF-α 受体信号通路之间的串扰对于确定 HIV 感染情况下神经元损伤的程度非常重要。我们将在两个具体目标的背景下检验这一假设。在第一个具体目标中，我们将确定 IGF-I 受体的阈值水平 神经保护所必需的，以及这种作用所需的受体信号传导域。在第二个具体目标中，我们将研究 IGF-I 和 TNF-α 信号通路以及负责 IGF-I 介导的神经保护的特定信号分子之间的相互作用。预期在本申请的背景下进行的研究将有助于基于IGF-I信号传导途径的利用和/或动员的新治疗策略的开发。