Signal Pathways Modulating HIV-1-induced Injury in CNS

HIV-1诱导的神经功能障碍代表了一系列复杂的事件，这些事件是由病毒与脑中宿主细胞之间的直接和间接交流引起的。直接机制包括HIV-1在小胶质细胞中的复制，以及在较小程度上在星形胶质细胞中的复制，而间接途径涉及影响神经元和其他脑细胞的病毒和细胞分泌因子。在这两种情况下，包括信号转导在内的一系列调节反应在破坏细胞功能中起着关键作用，这些细胞功能表现为病理性 特征如神经元和星形胶质细胞的凋亡;脱髓鞘;和中枢神经系统（CNS）内各种细胞的异常形态学外观。在这个项目中，我们把我们的注意力集中在信号转导通路，有可能在调制直接和间接途径参与艾滋病脑神经病理学的起源。在项目1（Amini，Peruzzi博士）中，提出了实验来研究病毒调节蛋白、达特和由感染细胞分泌的细胞调节剂对细胞增殖的影响。 神经元细胞中的NGF及其下游效应物。更具体地说，实验中提出的MAP激酶通路与cdKYp 35，神经元细胞分化和存活的重要调节因子的功能和物理相互作用的调查。在项目2（Reiss，Rappaport博士）中，将进行研究以评估神经元细胞分化期间肿瘤坏死因子-α（TNF-α）和胰岛素生长因子（IGF）通路之间的相互作用。更具体地说，我们将研究TNF-α的机制。 α通过激活Caspase 8抵消CNS细胞中IGF介导的信号传导的抗凋亡活性。在项目3（Sawaya、Khalili博士）中，重点是Wnt和TGF-β信号传导途径在控制小胶质细胞和星形胶质细胞中HIV-1基因表达和复制中的作用。更具体地说，将探索达特与Wnt途径的关键组分（包括TCF-4和β-连环蛋白）的协同相互作用，以及TGF-β的关键下游调节因子Smads和桥接Wnt和TGF-β调节功能的转录因子C/EBP的功能相互作用。神经病理学和组织培养核心（Drs. Del瓦莱，Gordon）将提供一个独特的基础设施，用于研究大脑中HIV-1失调的信号转导途径的各种组分的临床样本，并确定三个项目的结果与病理现实的生物学相关性。此外，该核心将是制备和分配各种神经细胞的可靠来源。在过去的五年中，该项目的参与者协同研究了HIV-1-CNS相互作用，将能够将这些分子研究的信息转化为理解决定神经细胞分化和死亡的基本机制，并利用其结果设计分子治疗策略来阻断病毒复制，并提高疾病过程中的神经元活力。

HIV-1 -induced neurological dysfunctions represent a complex series of events which result fiom direct and indirect communication between virus and host cells in the brain. The direct mechanism includes replication of HIV-1 in microglia, and to a lesser degree in astrocytes, whereas the indirect pathway involves viral and cellular secretory factors that impact upon neurons and other brain cells. In both events, a cascade of regulatory reactions including signal transduction plays a pivotal role in derailing cell functions that are manifested by pathological features such as apoptosis of neuronal and astrocytic cells; demyelination; and abnormal morphological appearance of various cells within the Central Nervous System (CNS). In this program project, we focus our attention on signal transduction pathways that have a potential in modulating direct and indirect pathways involved in the genesis of neuropathology in AIDS brain. In project 1 (Drs. Amini, Peruzzi), experiments are proposed to investigate the effect of viral regulatory protein, Tat and cellular modulators secreted by the infected cells upon NGF and its downstream effectors in neuronal cells. More specifically, experiments are proposed to investigate functional and physical interactions of factors within MAP kinase pathway with cdKYp35, the important regulator of neuronal cell differentiation and survival. In project 2 (Drs. Reiss, Rappaport), studies will be carried out to assess reciprocal talk between Tumor Necrosis Factor-alpha (TNF-alpha), and Insulin Growth Factor (IGF) pathways during neuronal cell differentiation. More specifically, we will investigate the mechanism whereby TNF- alpha via activation of Caspase 8 counteracts anti-apoptotic activity of IGF-mediated signaling in CNS cells. In project 3 (Drs. Sawaya, Khalili), the emphasis will be on the role of Wnt and TGF-beta signal transduction pathways in control of HIV-1 gene expression and replication in microglia and astrocytes. More specifically, the cooperative interaction of Tat with the key components of Wnt pathway, which includes TCF-4 and beta-Catenin, and the functional interaction of Smads, the critical downstream regulators of TGF-beta, and C/EBP, a transcription factor that bridges both Wnt and TGF-beta regulatory function, will be explored. The Neuropathology and Tissue Culture Core (Drs. Del Valle, Gordon), will provide a unique infrastructure to study clinical samples for the various components of the signal transduction pathways which are subject for deregulation by HIV-1 in brain, and determine the biological relevance of the results from the three projects with the pathological reality. Further, this core will be a reliable source for preparation and distribution of various neural cells. The participants of this program project who have worked synergistically to study HIV-1-CNS interactions during the last five years, will be able to convert the information fiom these molecular studies to understand the basic mechanisms that dictate neuronal cell differentiation and death, and utilize the outcome of this for devising molecular therapeutic strategies to block viral replication, and improve neuronal vitality during the course of the disease.