IGF induced neuronal protection and HIV-1 infection

中枢神经系统（CNS）疾病，包括痴呆，是艾滋病毒感染的常见并发症。尽管HAART治疗的出现最初降低了HIV感染（包括CNS异常）导致的发病率和死亡率，但近年来CNS疾病的发病率有所增加。这种增加可能部分代表HAART治疗的有效性下降，这是由于耐药菌株的流行以及CNS隔室中抗病毒药物的分布相对较差。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状况的增加表明开发额外的治疗方法的重要性。 治疗和/或预防病毒诱导的CNS损伤的策略。这里提出的研究集中在促进神经保护的主要途径，胰岛素样生长因子I（IGF-I）。几条证据表明，这种保护途径在HIV感染中受损，可能使神经元细胞以及其他细胞类型易受诱导的细胞因子和毒性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的有害作用的能力。 对分化神经元存活的影响。我们进一步表明，IGF-I受体（IGF-IR）在HIV相关性痴呆（HAD）患者中被激活，这是通过对组织标本进行免疫组织化学分析确定的，该组织标本具有对受体磷酸化（活性）形式的特异性抗体。这里提出的研究将测试的假设，即IGF-IR和TNF-α受体信号通路之间的串扰是重要的，在确定神经元损伤的程度，在艾滋病毒感染的背景下。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。预计在本申请背景下进行的研究将有助于开发基于IGF-I信号通路的利用和/或动员的新型治疗策略。

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.