Project #2. IGF-1 signaling pathway in HIV-1 CMS disorders.A significant number of HIV patients develop cognitive disorders and dementia. It is believed that cellularand viral factors released by the HIV-1 infected cells in the white matter, most notably TNFa , are responsiblefor neuronal injury seen in AIDS brains. Accordingly, we demonstrated that prolonged exposure ofdifferentiated neurons to TNFoc leads to the retraction of neuronal processes in the absence of neuronalapoptosis. HIV-1 infection can also compromise neuroprotective pathways including the insulin-like growthfactor 1 (IGF-1) signaling system. Accordingly, in earlier studies we demonstrated that IGF-1 protectsneurons from TNFa-induced retraction of neuronal processes. We have demonstrated that TNFa triggersserine phosphorylation of IRS-1 (pS-IRS-1) at the membrane rafts of differentiated neurons, and that pSIRS-1 interferes with integrin-mediated cellular responses, which are directly involved in the maintenance ofneuronal processes and neuronal outgrowth.These observations led us to hypothesize that in HIV encephalitis degeneration of neuronal processes iscaused by TNFa-induced interaction between pS-IRS-1 and neuronal integrins, which leads to detachmentand retraction of neuronal processes. This detrimental action of TNFoc is counteracted by IGF-l-mediatedtyrosine phosphorylation of IRS-1 (pY-IRS-1), which supports the binding of neuronal processes andfacilitates tissue remodeling and neuronal outgrowth. We have addressed this hypothesis by experimentsdescribed in three Specific Aims.
In Aim#1. we will analyze density of neuronal processes in the regions ofHIV encephalitis (HIVE) differentially affected by the accumulation of TNFoc.
In Aim#2. we will evaluateeffects of TNFcc on subcellular localization and phosphorylation status of IRS-1; and will analyze molecularinteractions between IRS-1, (31-integrin and ADAMs in primary neuronal cultures from the IGF-IR knockoutembryos and from age-matching non-transgenic littermates. Finally, in Aim#3. we will examine effects ofIGF-I stimulation on neuronal regeneration and tissue remodeling after TNFa -mediated retraction ofneuronal processes in differentiated neurosphere cultures from the IGF-IR knockout embryos and from agematchingnon-transgenic littermates. The outcome of this project will identify and characterize new molecularevents, which affect stability of neuronal processes in the paradigm of HIVE, and possibly other neurologicaldisorders characterized by the accumulation of TNFcc. Understanding the cross interaction between IGF-1and TNFa signaling pathways will help to develop new IGF-l-based therapeutic approaches againstneurological disorders in which retraction/degeneration of neuronal processes is a common event.
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