The role of gap junction channels in NeuroAIDS

描述（由申请人提供）：间隙连接（GJ）是细胞与邻近细胞的细胞质直接通信的唯一通道。在神经系统中，神经干细胞、神经元、星形胶质细胞、少突胶质细胞、血脑屏障细胞（内皮细胞和星形胶质细胞）以及炎症条件下的小胶质细胞表达GJ。这些通道的正常功能是传播细胞间信使，如钙、核苷酸、IPS、代谢物和电信号，最终协调组织稳态、增殖、分化、代谢和细胞死亡。迄今为止，人们对GJ在包括hiv感染在内的人类神经系统疾病的发病机制中所起的作用知之甚少。几乎所有的数据都是在小鼠和大鼠模型中获得的。我们使用人类细胞的初步数据是GJ可能积极参与神经艾滋病的第一个证据。我们建议它们放大由hiv感染的星形胶质细胞产生的毒性信号。我们的假设是，HIV感染的星形胶质细胞通过间隙连接的细胞间通讯将毒性和炎症信号传播到未感染的细胞中，从而损害其功能和活力，进一步导致中枢神经系统功能障碍。为了解决这一假设，提出了三个目标。目的1：确定星形胶质细胞中HIV感染维持或增强GJ表达的机制。目的2：确定hiv感染的星形胶质细胞和未感染的细胞之间的间隙连接通讯的病理生理后果。目的3：确定通过间隙连接扩散并改变未感染细胞功能的信号。这些研究的结果将有助于我们理解间隙连接通道在神经艾滋病发展中的作用，并可能为控制通常与hiv感染相关的神经变性提供新的策略。此外，这个提议对我来说是一个很好的机会，可以在一个很好的环境中接受训练，在Joan W. Berman博士的实验室，那里正在进行神经艾滋病的研究，以及在爱因斯坦医学院。

DESCRIPTION (provided by applicant): Gap junctions (GJ) are the only channels by which cells can communicate directly with the cytoplasm of neighboring cells. In the nervous system neuronal stem cells, neurons, astrocytes, oligodendrocytes, blood brain barrier cells (endothelial and astrocytes), and under inflammatory conditions, microglia express GJ. The normal function of these channels is to propagate intercellular messengers, such as calcium, nucleotides, IPS, metabolites, and electrical signals that ultimately coordinate tissue homeostasis, proliferation, differentiation, metabolism and cell death. To date little is known about the role that GJ play during the pathogenesis of human nervous system diseases, including HIV-infection. Almost all the data have been obtained in mouse and rat models. Our preliminary data, using human cells, are the first evidence that GJ may actively participate in NeuroAIDS. We propose that they amplify toxic signals generated by HIV-infected astrocytes. Our hypothesis is that HIV infected astrocytes use intercellular communication through gap junctions to spread toxic and inflammatory signals into uninfected cells to compromise their function and viability, leading further to CNS dysfunction. To address this hypothesis three Aims are proposed. Aim 1: To determine the mechanisms by which HIV- infection in astrocytes maintain or enhances or expression of GJ. Aim 2: To determine the pathophysiological consequences of gap junction communication between HIV-infected astrocytes and uninfected cells. Aim 3: To determine the signal (s) that diffuse through gap junctions to alter the function of uninfected cells. The results from these studies should contribute to our understanding of the role of gap junction channels in the development of NeuroAIDS, and may indicate new strategies to control the neurodegeneration often associated with HIV-infection. In addition, this proposal represents an outstanding opportunity for me to be trained in an outstanding environment, in the laboratory of Dr. Joan W. Berman, where studies of NeuroAIDS are ongoing, and at The Albert Einstein College of Medicine.