The long-term objective of this research is to understand the normal physiological function of IL-2 in brain, and to determine the role of this prototypic cytokine in pathophysiological processes of CNS. New theories and recent empirical data indicate that IL-2 may be involved in the pathogenesis of HIV-induced cognitive and neurobehavioral syndromes as well as other significant neuropsychiatric disorders (e.g., multiple sclerosis, Gullain-Barre syndrome, Alzheimer's disease, schizophrenia). This important immunoregulatory cytokine may also be pivotal in regulating other brain cytokines (e.g., IL-1, IL-6, TNF alpha) implicated in the pathophysiology of neuropsychiatric conditions such as HIV. Compelling evidence shows that IL-2 exerts prominent effects in the brains of animals and humans (e.g., cognitive, behavioral, neurochemical, neurotoxic), and appears to function as a neuromodulator. However, IL-2's fundamental site of action in brain, the IL-2 receptor (IL-2R) complex, is poorly understood. To this end, the laboratory of the P.I. was the first to clone and sequence cDNAs for subunits of the IL-2 receptor complex in brain, and assess the gene expression of these subunits by in situ hybridization histochemistry and ribonuclease protection methods. We have recently cloned a partial cDNA for the extracellular domain of the IL-2 beta (a subunit of the lymphocyte heterotimer complex which is known to be essential for intracellular signal transduction) and detected IL-2 beta message by in situ hybridization in the murine hippocampus. In addition, we recently cloned and sequenced a CDNA comprising the full length coding region of the IL-2R alpha accessory subunit from brain, and a partial brain IL-2R gamma cDNA. To determine the mechanism of action of IL-2 at the receptor level in the mammalian brain, the proposed studies will use molecular and pharmacological techniques to test the hypotheses: 1) that the subunits of the IL-2 receptor complex expressed by brain cells and lymphocytes are derived from the same gene coding sequences; 2) that there are subtypes of brain IL-2 receptors which are formed via differential expression of three distinct subunits (alpha, beta, and gamma); 3) that brain IL-2 receptor subtypes are localized to discrete anatomical regions, and; 4) that IL-2 receptors are expressed by neurons. In order to achieve the long-term objective of investigating systematically the physiological and pathophysiological effects of IL-2 in the CNS, the proposed studies are critical to establishing the fundamental molecular pharmacology and anatomy of brain IL-2 receptors. Successful completion of the proposed Specific Aims will then permit the testing of important hypotheses about the role of brain IL-2 receptors in pathophysiological processes relevant to HIV infection and multiple sclerosis (e.g., dysregulated CNS homeostatic and immune processes), schizophrenia (e.g., altered neurodevelopment), and Alzheimer's disease (e.g., neuronal degeneration).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034623-03
Application #
2431291
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1995-08-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1999-05-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Florida
Department
Psychiatry
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611