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Member Information
Dennis L. Kolson, MD, PhD
Associate Professor of Neurology
Office Phone: 215-573-3505
Office Fax: 215-573-2029
Email: kolsond@mail.med.upenn.edu
Website(s):
Education: MD 1985, University of Pittsburgh; PhD 1984, University of Pittsburgh
Keywords: HIV neuropathogenesis, Neuronal apoptosis, HIV/Neuronal and glial cell interactions, AIDS dementia
Research and/or Clinical Interests:
Determining the mechanisms and pathways of HIV-induced neuronal and glial cell dysfunction and apoptosis, and strategies for neuroprotection against HIV.
Summary:
My laboratory is focused upon pathogenesis of HIV-1-infection of the central nervous system (CNS). We utilize techniques of single-cell microdissection and mRNA expression analysis, and standard molecular biological approaches in our unique in vitro model to study mechanisms of neurodegeneration caused by HIV. Within the CNS, HIV productively infects macrophages and microglia, with subsequent neuronal loss by 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 apoptosis cascades. In addition, neuronal and glial seven-transmembrane (7TM) chemokine receptors may subserve both apoptotic and anti-apoptotic roles. Major unanswered questions include: i) what pathways are reponsible for neuronal apoptosis/damage and glial cell dysfunction in HIV infection?; ii) are specific genes turned on/off in neurons that are particularly vulnerable/resistant to HIV-induced apoptosis?; iii) what is the role of endogenous neuronal survival pathways in preventing HIV-induced damage?; iv) how can single-cell mRNA analysis be used to define patterns of gene expression in the brain to define mechanisms of neuronal death/damage and survival that may identify unique targets for neuroprotective strategies against HIV?
To address these questions, we have developed a unique human neuronal cell system utilizing NT2.N neurons in mixed neuronal/glial cell cultures to model HIV-1-induced neuronal apoptosis. We have examined the function of an orphan 7TM HIV co-receptor, APJ, in neurons, and found that it may serve a neuroprotective role against HIV. We have utilized single-cell microdissection and mRNA expression analyses to develop gene expression profiles in individual neurons in archival human brain. Our current projects involve in vitro and in vivo analysis of apoptosis pathways in neurons and glial cells that are induced by HIV-infected macrophages, analysis of the pathways of APJ receptor-mediated neuroprotective responses, and in vivo analysis of neuronal and glial gene expression in HIV-infected brain through single-cell mRNA analysis.
Representative Publications:
Kolson DL, Sabnekar P, Baybis M and Crino PB. Gene expression in TUNEL-positive neurons in HIV-infected brain. J.Neurovirol. (in press).
Patel SH, Inglese M, Glosser G, Kolson DL, Grossman RI and Gonen O. Whole-brain N-acetylaspartate level versus cognitive perfomance in HIV infection. Am. J. Neuroradiol. 24: 1587-1591. 2003.
Yi Y, Chen W, Frank I, Cutilli J, Singh A, Starr-Spires L, Sulcove J, Kolson DL and Collman RG. An unusial syncytium-inducing human immunodeficiency virus type 1 primary isolate from the central nervous system that is restricted to CXCR4, replicates efficiently in primary macrophages, and induces neuronal apoptosis. J. Neurovirol. 9: 432-441. 2003.
Chen W, Sulcove J, Jaffer S, Frank I, Ozdener H and Kolson DL . Development of a human neuronal cell model for HIV/Macrophage -induced neurotoxicity: apoptosis induced by primary HIV-1 primary isolates and evidence for involvement of the Bcl-2/Bcl-xL-senstivie intrinsic apoptosis pathway. J. Virology 76: 9407-9419. 2002.
Kolson DL . Neuropathogenesis of central nervous system HIV-1 infection. Clin. Lab. Med. 22: 1-15. 2002.
Singh A, Yi Y, Isaacs SN, Kolson DL and Collman RG. Concordant utilization of macrophage entry coreceptors by related variants within an HIV-1 primary isolate viral swarm. AIDS Res. Hum. Retrovir. AIDS Res. Hum. Retroviruses. 17: 957-963. 2001.
Coughlan CM, McManus CM, Sharron M, Gao Z-Y, Murphy D, Jaffer S, Choe W, Chen W, Hesselgesser J, Gaylord H, Kalyuzhny A, Lee V M-Y, Wolf B, Doms RW and Kolson DL. Expression of multiple functional chemokine receptors and MCP-1 chemokine in human neurons. Neuroscience 97: 591-600. 2000.
Choe W, Albright A, Jaffer S, Hesselgesser J, Lavi E, Crino P and Kolson DL . Functional expression of the seven-transmembrane HIV-1 co-receptor APJ in neural cells. J.Neurovirology 6: S61-S69. 2000.
Hesselgesser,J., Taub,D., Baskar,P., Greenberg,M., Hoxie,J., Kolson,D.L . and Horuk,R. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 a is mediated by the chemokine receptor CXCR4. Curr. Biol. 8: 595-598. 1998.
Kolson,D.L ., Lavi,E. and Gonzalez-Scarano,F. The effects of HIV in the central nervous system. Adv.Virus Res. 50: 1-47. 1998.
