Neuronal degeneration and lymphocyte death are hallmarks of AIDS. Such cellular cytotoxicity is thought to be mediated, in part, by gp120 of the human immunodeficiency virus (HIV) causing an influx of Ca++ into neuronal cells and lymphocytes. This proposal is concerned with the development of a series of blockers of Ca++ entry that will be based on a novel peptide (termed Ca-like peptide, CALP) which inhibits Ca++ influx into gp120 treated human lymphocytes and protects them against HIV as well as gp120 mediated cytotoxicity. CALP also blocks lymphocytotoxicity and apoptosis in feline immunodeficiency virus (FIV)-infected cat peripheral blood mononuclear cells. Furthermore, the peptide blocks gp120-mediated killing of rat neocortical neurons. CALP is particularly intriguing because it can inhibit or facilitate Ca++ entry and lymphocyte mitogenesis depending on the cell type and/or stimulus. The current proposal involves a crossdisciplinary, multi-investigator initiative that applies biologic, biochemical, and structural procedures to the cytotoxic aspect of AIDS. Specifically, the investigators will test the ability of CALP to inhibit FIV, HIV, and gp120- induced neurotoxicity and apoptosis as well as to determine if these effects are mediated through inhibition of Ca++ regulated pathways. Peptide and nonpeptide analogues of CALP with possible increased activity, and desirable pharmacologic properties will be synthesized based on the investigators knowledge of the solution structure of CALP and its complex with the prototypical Ca++ binding protein, calmodulin (CAM). This will be accomplished through the use of 2, 3, and 4D nuclear magnetic resonance (NMR) spectroscopy to study CALP, CALP analogues, and their interaction with CAM and CAM fragments. Successful completion of these studies should yield a novel class of pharmacologic agents with therapeutic potential for certain neurologic and immunologic sequelae of AIDS, as well as having considerable utility for the study of Ca++-regulated pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH052527-04
Application #
2609471
Study Section
Special Emphasis Panel (SRCM (01))
Program Officer
Rausch, Dianne M
Project Start
1994-12-01
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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