Signal Pathways Modulating HIV-1-induced Injury in CNS

HIV-1诱导的神经功能障碍是一系列复杂的事件，导致病毒与大脑中宿主细胞之间的直接和间接通信。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。在这两个事件中，包括信号转导在内的一系列调节反应在使病理表现的细胞功能脱轨中起着关键作用。 例如神经细胞和星形胶质细胞的凋亡；脱髓鞘；以及中枢神经系统(CNS)内各种细胞的异常形态外观。在这个项目中，我们把注意力集中在信号转导通路上，这些通路有可能调节参与艾滋病脑内神经病理发生的直接和间接通路。在项目1(Dr.Amini，Peruzzi)中，建议进行实验以调查受感染细胞分泌的病毒调节蛋白、Tat和细胞调节剂对 神经细胞中的NGF及其下游效应分子。更具体地说，实验是为了研究MAP激酶通路中的因子与cdKYp35之间的功能和物理相互作用。cdKYp35是神经细胞分化和存活的重要调节因子。在项目2(Reiss博士，RapPaport)中，将开展研究以评估神经细胞分化过程中肿瘤坏死因子-α(TNF-α)和胰岛素生长因子(IGF)途径之间的相互作用。更具体地说，我们将研究肿瘤坏死因子- α通过激活Caspase8在中枢神经系统细胞中抵消IGF介导的信号的抗凋亡活性。在项目3(Sawaya博士，Khalili博士)中，重点将放在Wnt和转化生长因子-β信号转导通路在控制HIV-1基因在小胶质细胞和星形胶质细胞中的表达和复制中的作用。更具体地说，将探索Tat与Wnt途径的关键成分(包括TCF-4和β-catenin)的协同作用，以及转化生长因子-β的关键下游调节因子Smads和连接Wnt和转化生长因子-β调控功能的转录因子C/EBP的功能相互作用。神经病理学和组织培养核心(Drs.Del Valle，Gordon)将提供独特的基础设施，研究大脑中HIV-1放松调控的信号转导通路的各个组成部分的临床样本，并确定三个项目的结果与病理现实的生物学相关性。此外，这个核心将是各种神经细胞制备和分布的可靠来源。该计划项目的参与者在过去五年中协同研究HIV-1-CNS相互作用，将能够将这些分子研究中的信息转化为了解支配神经细胞分化和死亡的基本机制，并利用这一结果设计分子治疗策略来阻止病毒复制，并在疾病过程中提高神经元活力。

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.