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. ? ? ?
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