The neurocognitive alterations in HIV disease are associated with neurodegeneration of selective neuronal populations. Survival of these populations are dependent on specific trophic factors, such as fibroblast growth factor (FGF). In this context, it is possible that dysregulation of patterns of FGF expression in individuals with AIDS might render neurons more vulnerable to degeneration under the combined challenge of excitotoxins and viral products. Thus, the main objective of this proposal is to investigate mechanisms of FGF1 neuroprotection in HIV disease. The central hypothesis is that neuroprotective effects of FGF 1 against HIV products (e.g.: Tat and gp 120) are mediated in the short term via regulation of glycogen synthase kinase 3 13 (GSK313), a modulator of cell death pathways (53) and in the long term by regulating the expression of chemokine receptors (e.g.: CXCR4) that mediate HIV toxicity. The following Specific Aims are proposed: 1) To determine if patterns of FGF1 expression in the brains of AIDS patients are associated with neuroprotection vs. neurodegeneration. For this purpose levels of FGFI, FGF receptor 1 (FGFRI), GSK313, 13-catenin and CXCR4 will be determined in AIDS brains subdivided into four groups based on the presence or absence of neurodegeneration and HIVE. 2) To determine if FGF1 is neuroprotective in vivo against HIV-products. In order to test this hypothesis in vivo, transgenic (tg) mice overexpressing FGF1 will be generated and crossbred with gpl20 or Tat tg mice. Additional experiments will be performed where FGF1 tg mice will receive intracerebral injections of gpl20 or Tat. Levels of neurodegeneration and GSK313, g-catenin and CXCR4 will be compared among mice. 3) To determine the mechanisms responsible for FGF1 neuroprotective effects against HIV neurotoxicity. For this purpose, expression of GSK313, 13- catenin and CXCR4 will be deternained in human fetal primary neurons in the presence or absence of FGF1 and gpl2 and Tat. Neurodegeneration will be assesed by lactase dehydrogenase (LDH), MTT, DNA fragmentation and caspase activation assays. The involvement of the intracellular signaling pathways will be further evaluated via inhibition or activation of FGFR1 or GSK313. These studies will be performed primarily at the Institute of Psychiatry in London. Clarification of the mechanisms by which FGF1 protects neurons against HIV will provide a potential target for the development of new treatment directed at ameliorating the neuronal damage to in AIDS patients with cognitive impairment.
Showing the most recent 10 out of 55 publications
