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Dr. Kolson is a Penn Medicine physician who is employed by or has a contract with the Clinical Practices of the University of Pennsylvania.
multiple sclerosis, neurological complication of AIDS
Penn Neuroscience Center
Perelman Center for Advanced Medicine
South Pavilion, 2nd Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104
A facility of the Hospital of the University of Pennsylvania
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
280C Clinical Research Building
University of Pennsylvania
415 Curie Blvd.
Philadelphia, PA 19104/6146
Office Phone: 215-573-3505
Patient Appointments: 800-789-PENN (7366)
Philadelphia, PA 800-789-PENN © 2015,
The Trustees of the University of Pennsylvania