Despite recent advances in antiretroviral therapies, the effect of human immunodeficiency virus type one (HIV-1) on the central nervous system remains a significant cause of morbidity in affected humans. The pathogenesis of the cognitive dysfunction associated with brain disease likely revolves around productive HIV infection of brain macrophages/microglia leading to the secretion of an inflammatory cascade for neurodegreneration. The hypothesis proposed in this application is that virus-infected immunologically competent brain macrophages and microglia play central but distinctive roles in HIV-1 neuropathogenesis. This mentored clinical scientist application is designed for 5 years of support for career development from a physician to a fully competent independent scientist in academic medicine. The goal of the program is to learn the necessary technical and didactic skills to perform hypothesis-driven research. Knowledge in molecular genetics, biochemistry, immunology, neurobiology, and medical ethics through specific laboratory rotations and coursework will be initiated at both the University of Nebraska Medical Center and at Creighton University. Research activities will take place within an integrated program at the Center for Neurovirology and Neurodegenerative Disorders. Mentored research will evolve from closely supervised works into fully independent research activities. The analysis of the molecular mechanisms of HIV-1 encephalitis will involve developmental laboratory and animal model systems, drug testing and combined research activities in neuroimmunology, virology, molecular genetics and pathology. This, taken together with coursework, broad university, clinical and center support aims to permit a research experience of the highest order for grasping the principals necessary for sustained success in academic biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH001552-02
Application #
2883341
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Program Officer
Rausch, Dianne M
Project Start
1998-05-01
Project End
2003-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Carlson, Kimberly A; Limoges, Jenae; Pohlman, Garrett D et al. (2004) OTK18 expression in brain mononuclear phagocytes parallels the severity of HIV-1 encephalitis. J Neuroimmunol 150:186-98
Carlson, Kimberly A; Leisman, Gary; Limoges, Jenae et al. (2004) Molecular characterization of a putative antiretroviral transcriptional factor, OTK18. J Immunol 172:381-91
Nukuna, Adeline; Gendelman, Howard E; Limoges, Jenae et al. (2004) Levels of human immunodeficiency virus type 1 (HIV-1) replication in macrophages determines the severity of murine HIV-1 encephalitis. J Neurovirol 10 Suppl 1:82-90
Persidsky, Y; Limoges, J; Rasmussen, J et al. (2001) Reduction in glial immunity and neuropathology by a PAF antagonist and an MMP and TNFalpha inhibitor in SCID mice with HIV-1 encephalitis. J Neuroimmunol 114:57-68
Limoges, J; Poluektova, L; Ratanasuwan, W et al. (2001) The efficacy of potent anti-retroviral drug combinations tested in a murine model of HIV-1 encephalitis. Virology 281:21-34
Limoges, J; Persidsky, Y; Poluektova, L et al. (2000) Evaluation of antiretroviral drug efficacy for HIV-1 encephalitis in SCID mice. Neurology 54:379-89
Persidsky, Y; Ghorpade, A; Rasmussen, J et al. (1999) Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1599-611