Description of Research Expertise:
Mechansims and determinants of HIV induced neuronal injury. Neuronal cell responses to virus induced injury.
Key words: neuron, hippocampus, apoptosis, gene expression, single-cell mRNA, HIV, chemokine receptor, NMDA receptor.
Description of Research
My laboratory is focused upon pathogenesis of HIV-1-infection of the central nervous system (CNS) as a model for neuroimmune-mediated neurodegeneration. Within the CNS, HIV productively infects macrophages and microglia, with subsequent neuronal damage and loss by several mechanisms, including NMDA receptor mediated excitotoxicity and apoptosis. In vitro modeling shows that such infection results in the release of soluble neurotoxins that act in part through activation of neuronal NMDA receptors with subsequent activation of cell death pathways, including apoptosis cascades and calpain activation. Specific NMDA receptor subunits (NR2A, NR2B) are critical for such degeneration. In addition, dysregulation of glial (astrocyte, macrophage) neurotransmitter and oxidative functions may subserve both apoptotic and anti-apoptotic roles. HIV infection initiates neurodegeneration through mechanisms that are shared by other neurodegenerative diseases and understanding these mechanims has broad therapeutic implications for other such diseases.
Interestingly, neurons appear to initiate pro-survival resoponses to injury that involve release of neuropeptides and chemokines. We are focusing on one such unique neuropeptide, apelin, and its cognate receptor, APJ and the novel role that this receptor/ligand interaction might play in modulating neuronal responses to injury. We have found that apelin peptide is released by injury hippocampal and cortical neurons (in addition to physiological relase from pituicytes) and that it can modulate NMDA receptor function through phosphorylation, internalization, and suppression of NMDA receptors. We are thus focusing on how neuronal cell function is modulated by virally-induced stress responses in the CNS and how this applies to neurodegeneration, and how HIV infection might mimic other degenerative conditions. Major unanswered questions include:
1. What pathways are reponsible for neuronal damage and glial cell dysfunction in HIV infection?
2. How can NMDA receptor modulation alter neuronal susceptibility to HIV-induced damage?
3. Are specific genes turned on/off in neurons that are particularly vulnerable/resistant to HIV-induced injury?
4. What is the role of endogenous neuronal survival pathways (apelin/APJ) in preventing HIV-induced damage?
5. How can in vitro modeling be used to define targets for neuroprotection against HIV-1 and other neurodegenerative diseases?
6. How does the unfolded protein response (UPR) in HIV-infected macrophages modulate neurodegeneration?
To address these questions, we have developed several in vitro neuronal cell culture systems. We utilize primary rodent hippocampal and neocortical cell cultures as well as a unique human neuronal cell system utilizing NT2.N neurons in mixed neuronal/glial cell cultures to model HIV-1-induced neurodegeneration. We have developed a novel in vitro model using mixed cultures of human monocyte-derived macrophages with rodent neurons and astrocytes to analyze effects of HIV infection in the central nervous system. We have found that developmental susceptibility to HIV-1-induced neurodegeneration is determined by NMDA receptor subunit expression, and that the macrophage kynurenine metabolic pathway is a major contributor to the production of HIV-1-induced excitotoxin expression. We have also demonstrated that excitotoxic injury to neurons induces release of a novel neuropeptide, apelin, that can promote neuronal survival through modulation of NMDA receptors. Our current projects involve in vitro and in vivo analysis of cell death pathways in neurons that are induced by HIV-infected macrophages, analysis of the role of specific NMDA receptor subunits in determining neuronal vulnerability to HIV-induced damage, analysis of the unfolded protein response in macrophages and how it modulates neurodegeneration, and how apelin neuropeptide alters cellular responses through NMDA receptor modulation.
1. Analysis of NMDA receptor subunit expression and phosphorylation patterns in hippocampal and cortical neurons susceptible to HIV neurotoxicity
2. Analysis of the macrophage unfolded protein response.
3. Identification of the downstream pathways of death in neurons by HIV-1, including the role of calpain activation.
4. Analysis of apelin/APJ function in neural cells.
Patricia Vance, MS - Research Specialist
Lorraine Kolson, BS - Research Specialist
Denise Cook - Neuroscience PhD student
Stephanie Cross, Neuroscience MD/PhD student
Kolson DL, Sabnekar P: Gene expression in TUNEL-positive Neurons in HIV-infected brain J. Neurovirol. 10 ((suppl. 1)): 102-7,2004.
Patel SH, Kolson DL, Glosser G, Matozzo I, Ge Y, Babb JS: Correlation between percentage of brain parenchymal volume and neurocognitive performance in HIV infected patients. Am. J. Neuroradiol. 23 : 543-549,2002.
Chen W, Sulcove J, Frank I, Jaffer S: Development of a human neuronal cell model for HIV/macrophage-induced neurotoxicity: apoptosis induced by HIV-1 primary isolates and evidence for involvement of the Bcl-2/Bcl-xL-sensitive intrinsic apoptosis pathway. J. Virology 76 : 9407-9419,2002.
Ge Y, Grossman RI, Babb JS, Rabin ML: Age-related total gray matter and white matter changes in normal adult brain. Part I. Volumetric MR imaging analysis. Am. J. Neuroradiol. 23 : 1327-1333,2002.
Ge Y, Grossman RI, Babb JS, Rabin ML: Age-related total gray matter and white matter changes in normal adult brain. Part II: quantitative magnetization transfer ratio histogram analysis. Am. J. Neuroradiol. 23 : 1334-1341,2002.
O’Donnell, LA, Chen W, Agrawal A: Potential neuroprotective role of APJ/apelin interactions: protection against HIV-induced apoptosis. NIMH workshop: Viral and Host Genetic Factyors Regulating HIV/CNS Disease, Rockville, MD. : 2002.
Martin-Garcia J, Kolson DL: Chemokine receptors in the brain: their role in HIV infection and pathogenesis. AIDS (in press). : 2002.
Neuropathogenesis of central nervous system HIV-1 infection. Clin. Lab. Med. 22 : 1-15,2002.
Ge Y, Grossman RL, Udupa JK, Babb JS: Magnetization transfer ratio histogram analysis of gray matter in relapsing-remitting multiple sclerosis. Am. J. Neuroradiol. 22 : 470-475,2001.
Ge Y, Grossman RL, Udupa JK, Babb JS: Brain atrophy in relapsing-remitting multiple sclerosis: fractional volumetric analysis of gray matter and white matter. Radiology 220 : 606-610,2001.
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