Nitric oxide (NO) is a messenger molecule of neurons that plays a role in diverse physiological and pathophysiologic processes, including glutamate neurotoxicity, neurodegeneration and long-term potentiation. Targeted disruption of the neuronal nitric oxide synthase (nNOS) gene results in dilated stomachs and hypertrophied pyloric sphincter muscles, a phenotype that resembles diabetic gastroparesis. The gross anatomic disturbance in nNOS-/- mice suggests that NO may regulate gastropyloric function. We will use phenol red spectrophotometry and ex-vivo organ bath experiments to determine the role of NO neurotransmission in the regulation of gastric emptying and gastropyloric function. We will also ascertain the role of nNOS in gastropyloric dysfunction of diabetic mice. Preliminary results demonstrate that diabetic and nNOS-/- mice exhibit similar physiologic phenotypes. This suggests that abnormal NO function might underlie the disturbances in diabetic animals. We will study nNOS protein mRNA expression in tissue preparations and cultured enteric neurons to establish the molecular basis for enteric nervous system (ENS) nNOS down-regulation in diabetes. Initial results demonstrate that nNOS protein expression is increased in the presence of insulin. We will use cultured enteric neurons, primary cortical neurons and cerebellar granule cells as models to determine the role of insulin, insulin growth factors (IGFs) and their receptors in nNOS expression and regulation in the ENS and CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30MH012545-01
Application #
6015393
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Goldschmidts, Walter L
Project Start
2000-12-01
Project End
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218