Nitric oxide (NO) is an important mediator of cerebral blood flow and cerebral metabolism. During the previous funding periods, we generated knockout mice for the nNOS gene and the eNOS gene. We used these mice to define the physiologic roles of NO in the brain, and the vascular and toxic effects of NO following cerebral ischemia. We also made tissue-specific gene knockouts for the nNOS gene, targeting gene deletion to the CA1 neurons of the hippocampus, in order to study the role of NO production by individual cells in the response to global ischemia. We now propose to use a combination of transgenic, standard and tissue-specific gene knockout mouse models to define the specific molecular pathways by which NO confers resistance to ischemia, both at baseline, and in ischemic preconditioning. Our hypothesis is that nNOS is required to activate two specific neuroprotective pathways: the Raf/MEKIERK pathway, and the Pl3kinase/Akt pathway, while eNOS is involved in mediating protection, in part by blood flow effects. We hope to understand these naturally occurring protective mechanisms, so that we may harness them to treat and or prophylax against tissue damage from cerebral ischemia.
Our specific aims are to: 1. Test the hypothesis that nNOS activates the Raf/MEK/ERK and Pl3-kinase/Akt pathways to reduce damage both from global ischemia, and from ischemic preconditioning. 2. Test the hypothesis that modulation of eNOS activity by phosphorylation and blood flow effects contribute to ischemic preconditioning protection. 3. Test the hypothesis that Akt activation mediates neuroprotection in ischemic preconditioning and in global ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033335-12
Application #
6898181
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (02))
Program Officer
Golanov, Eugene V
Project Start
1994-09-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
12
Fiscal Year
2005
Total Cost
$355,395
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Turcot, Valérie (see original citation for additional authors) (2018) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 50:26-41
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