TAT induced deregulation of neuronal differentiation and survival by NGF

TAT 诱导 NGF 对神经元分化和存活的失调

• 批准号: 6672685
• 负责人: SHOHREH AMINI
• 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/6672685
• 关键词: AIDS /HIV neuropathy; DNA binding protein; PC12 cells; biological signal transduction; cell differentiation; cell growth regulation; cyclin dependent kinase; human immunodeficiency virus 1; mitogen activated protein kinase; nerve growth factors; neurogenesis; protein protein interaction; regulatory gene; tissue /cell culture; virus genetics

Infection with human immunodeficiency virus type 1 (HIV-1) can cause dementia in greater than 30% of AIDS patients. HIV-1 enters the brain at the early stage of infection and resides primarily in a limited number of macrophages/microglia and astrocytes. Infection of these cells, however, may not explain the massive neuronal pathology which is seen in AIDS associated dementia suggesting a role for factors from HIV-1 and infected cells that trigger a cascade of events leading to neurodegeneration. One of the viral proteins which possesses a strong regulatory activity is Tat, which is secreted by infected cells and can be taken up by neighboring uninfected cells. Results from our recent studies show that Tat can influence multiple biological events that lead to neuronal injury. For example, treatment of neuronal cells with Tat affects MAPWERK1/2 activity, the downstream central component of the nerve growth factor (NGF) signaling pathway. This can affect Egr-I, a transcription factor which is regulated by MAPWEMU2 and is responsible for the stimulation of p35 protein. p35 is a neuron-specific activator of cdk5, a cyclin dependent kinase which phosphorylates several neuronal proteins including neurofilament and plays an important role in neuronal differentiation and survival. Accordingly, our data indicate that treatment of cells with Tat severely decreases p35 expression. In parallel, Tat can bind to the cellular protein, Pura, which associates with cdk5. Results from Pura knockout animals revealed a decrease in p35 activity, pointing to the importance of Pura association with cdk5 in the activity of cdk5:p35 complex. These observations provide a strong rationale for launching a comprehensive series of experiments to investigate the cooperativity between HIV- 1 Tat and the cellular protein, Puralpha, which results in de-regulation of the NGF signal transduction pathway in neuronal cells. Results from the proposed studies in this project should unravel several biological pathways which are affected by HIV- 1 leading to neurodegeneration and dementia, and assist us in devising a neuroprotective strategy toward treatment of HIV- 1 induced neuronal injury.

人类免疫缺陷病毒1型（HIV-1）的感染会导致大于30％的艾滋病患者的痴呆。 HIV-1在感染的早期进入大脑，主要驻留在有限数量的巨噬细胞/小胶质细胞和星形胶质细胞中。然而，这些细胞的感染可能无法解释与艾滋病相关的痴呆症中看到的大规模神经元病理学，这表明HIV-1和受感染细胞的因素的作用触发了导致神经变性的一系列事件。具有强烈调节活性的病毒蛋白之一是TAT，由感染细胞分泌，可以被邻近未感染的细胞吸收。我们最近的研究的结果表明，TAT会影响导致神经元损伤的多个生物学事件。例如，用TAT处理神经元细胞会影响MapWerk1/2 活性是神经生长因子（NGF）信号通路的下游中心成分。这可能会影响EGR-I，这是一个由MAPWEMU2调节的转录因子，并负责刺激p35蛋白。 p35是CDK5的神经元特异性激活剂，CDK5是一种依赖细胞周期蛋白的激酶，它磷酸化了几种神经元蛋白，包括神经丝，并在神经元分化和存活中起重要作用。因此，我们的数据表明，用TAT处理细胞会严重降低p35的表达。同时，TAT可以与CDK5相关的细胞蛋白Pura结合。 PURA敲除动物的结果显示，p35活性的降低，表明Pura与CDK5在CDK5：p35复合物的活性中的重要性。这些观察结果为启动一系列全面的实验提供了强大的理由，以研究HIV-1 TAT与细胞蛋白Puralpha之间的合作性，从而导致神经元细胞中NGF信号转导途径的下调。该项目中提出的研究的结果应揭示几种受HIV-1影响导致神经变性和痴呆症的生物学途径，并帮助我们制定神经保护策略来治疗HIV-1诱导的神经元损伤。