Individuals infected with the human immunodeficiency virus (HIV) frequently exhibit serious, progressive behavioral, cognitive and motor deficits (termed AIDS Dementia Complex - ADC) in association with pathological changes (including gliosis, encephalitis and vacuolar myelopathy in the brain. Despite widespread neurological deficits, the virus is restricted in distribution to neural cells having a monocyte/macrophage lineage and is thought not to infect neuronal cells, implying that the mechanism of HIV-associated disease is probably indirect, mediated by toxic factors produced as a result of or in response to the viral infection. In this context an attractive hypothesis is that cytokines, produced either by infiltrating immunoinflammatory cells or by resident brain cells, via their ability to regulate the growth and functions of glial and neuronal cells are key mediators of pathology in ADC. This proposal will investigate the effects of three such cytokines - interleukin-6(IL-6), tumor necrosis factor - alpha(TNF-alpha) and interleukin-3(IL-3) to induce CNS pathology in vivo. We will use the transgenic approach to target the expression of IL-6, TNF-alpha proteins to CNS astrocytes in the mouse using a glial fibrillary acidic protein (GFAP) based expression vector. Through this approach we aim to reproduce aspects of the pathology seen in ADC and correlate these with clinical changes. In addition, interactions between pathogenetic factors will be examined in transgenic lines of mice by inducing further CNS insults e.g. stab wound injury or infection with neurotropic agents, as well as crossing lines of mice expressing different transgenes. Finally in order to gain an understanding of the neurological and behavioral impact of over-expressing cytokines in the CNS, transgenic mice will be subject to electrophysiological and behavioral testing. The studies outlined in this proposal will establish murine models to examine the pathophysiological consequences of inappropriately expressing cytokines in the CNS. They should provide important insights into what currently remains a mystery i.e. the molecular basis for ADC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH050426-01
Application #
3389592
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Project Start
1993-02-01
Project End
1996-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Campbell, Iain L; Hofer, Markus J; Pagenstecher, Axel (2010) Transgenic models for cytokine-induced neurological disease. Biochim Biophys Acta 1802:903-17
Carrasco, Javier; Penkowa, Milena; Giralt, Mercedes et al. (2003) Role of metallothionein-III following central nervous system damage. Neurobiol Dis 13:22-36
Samland, Helen; Huitron-Resendiz, Salvador; Masliah, Eliezer et al. (2003) Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6. J Neurosci Res 73:176-87
Molinero, Amalia; Penkowa, Milena; Hernandez, Joaquin et al. (2003) Metallothionein-I overexpression decreases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin-6. J Neuropathol Exp Neurol 62:315-28
Penkowa, Milena; Camats, Jordi; Giralt, Mercedes et al. (2003) Metallothionein-I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte-targeted interleukin-6 expression. Glia 42:287-306
Campbell, I L (2002) Cytokine-mediated inflammation and other actions in the central nervous system. Ernst Schering Res Found Workshop :61-83
Wang, J; Asensio, V C; Campbell, I L (2002) Cytokines and chemokines as mediators of protection and injury in the central nervous system assessed in transgenic mice. Curr Top Microbiol Immunol 265:23-48
Strack, Andreas; Schluter, Dirk; Asensio, Valerie C et al. (2002) Regulation of the kinetics of intracerebral chemokine gene expression in murine Toxoplasma encephalitis: impact of host genetic factors. Glia 40:372-7
Strack, Andreas; Asensio, Valerie C; Campbell, Iain L et al. (2002) Chemokines are differentially expressed by astrocytes, microglia and inflammatory leukocytes in Toxoplasma encephalitis and critically regulated by interferon-gamma. Acta Neuropathol (Berl) 103:458-68
Milner, Richard; Campbell, Iain L (2002) Cytokines regulate microglial adhesion to laminin and astrocyte extracellular matrix via protein kinase C-dependent activation of the alpha6beta1 integrin. J Neurosci 22:1562-72

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