This research focuses on a recently discovered effect of opiates - i.e. their ability to regulate the protein ferritin heavy chain (FHC) in neurons - andits contribution to HIV neuropathology. The specific objectives of this proposal are: a) to collect evidence of FHC changes in the brain of opiate drug users (DU) and examine the potential role of FHC in HIV neuropathology, and b) to elucidate the mechanisms involved in the regulation of neuronal FHC expression by morphine. The long-term goal of this research is to further explore the biological basis of neuronal dysfunction in HIV/DU patients. The general hypothesis to be tested is that opiate abuse exacerbates HIV neuropathology by rendering neurons more vulnerable to toxic stimuli and/or by altering their ability of responding to damaging insults. Mechanistically, this could be caused by abnormal increase of FHC in neurons and consequent impairment of the protective actions of the chemokine/receptor pair CXCL12/CXCR4. To test these hypotheses powerful techniques, i.e. Multispectral Imaging and Laser Capture Microdissection, along with in vitro and in vivo/ex vivo experimental approaches are proposed, within three specific aims. Studies in aim 1 focus on the expression of FHC in autopsy brain tissue from HIV/DU patients - with the primary intent of establishing whether drug abuse alters FHC levels in the human brain, mainly in cortical neurons. These studies are also expected to provide information about the correlation of FHC changes with neurological disorders in HIV/DU patients. The experiments discussed in aim 2 focuses on the consequences of morphine-induced FHC on CXCR4 function in animal brain tissue and cortical neurons in culture. The goal is to complement aim 1 studies with controlled experiments that are not feasible in humans. These studies will investigate the cellular (i.e. neurons/glia) and subcellular (cytosol /nucleus) distribution of FHC in response to morphine, which influence FHC ability to interact with and modulate CXCR4, and the mechanisms involved. Finally, aim 3 will tackle the molecular mechanisms involved in the action of morphine and HIV on FHC (such as posttranscriptional regulation of FHC and the role of ferritin iron binding properties), which is an important step toward understanding of the biological implications of this novel action of morphine in the context of HIV neuropathology. Overall, the proposed research will provide essential information about a novel role of FHC as a regulator of neuronal function and survival, determine if this protein is a relevant target of opiate action on neurons, and characterize both the consequences of this action and some of the mechanisms involved in neuropathology. By characterizing the role of FHC in neuronal dysfunction and identifying the mechanistic basis of opiates action on FHC regulation, this research will provide new avenues for therapeutic intervention aimed at preventing or reducing the neurological complications of HIV infection.
Despite the benefits of current antiretroviral treatments, the neurological complications of HIV infection, which include both neurocognitive and motor/sensory deficits, remain an unmet medical and social need - partly because the biological bases of these complex disorders are still undefined. The studies proposed in this application will characterize specific effects of opiates on neurons that interfere with normal neuronal function and may contribute to neuronal alteration and HIV neurocognitive impairment. As such, this research will offer new therapeutic strategies aimed at reducing the neurological complications of HIV infection in drug users, a significant group of HIV-infected patients in modern times, as well as provide new insights for best management of HIV patients in general.
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