Nitric oxide (NO) is a gaseous messenger synthesized from L-arginine and molecular oxygen by three structurally distinct nitric oxide synthases (NOS): neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Under normal conditions, NO plays key roles in homeostasis. In stroke, NO overproduction by nNOS results in significant neurotoxicity, while NO generated by eNOS is beneficial to restoring blood flow via vasodilation and inhibition of platelet aggregation, nNOS is an excellent molecular target for stroke therapy, but inhibitors must be clearly selective for the nNOS isoform such that they do not block the positive effects resulting from NO production by eNOS. The hypotheses underlying this research project are that 1) comparative structural study of the nNOS and eNOS isoforms will identify differences, which can be targeted for isoform specific inhibition of nNOS and 2) an understanding of the structural basis of inhibition of a natural NOS inhibitor may provide novel NOS inhibition strategies. The structural basis of nNOS inhibition will be probed by high resolution x-ray crystallographic studies addressing three Specific Aims: 1) the determination of the three dimensional structure of the catalytic heme domain of nNOS, 2) characterization and comparison of nNOS specific isoform derivatives bound to the nNOS and eNOS home domain, and 3) determination of the NOS recognition site of a natural protein inhibitor, caveolin-1. These studies will provide the basic science framework for nNOS isoform specific drug design. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS046139-03
Application #
6893671
Study Section
NST-2 Subcommittee (NST)
Program Officer
Stewart, Randall R
Project Start
2003-05-15
Project End
2006-10-14
Budget Start
2005-05-15
Budget End
2006-05-14
Support Year
3
Fiscal Year
2005
Total Cost
$26,256
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225