Variation in neurotransmitter transporters, receptors and abnormal levels of neurotransmitters potentially are involved in neurological diseases including schizophrenia, bipolar affective disorder, autism, affective disorder, late onset Alzheimer's disease, Parkinson's disease and others. Fundamental information characterizing human neurotransmitter metabolism associated with neurodegenerative diseases could provide new approaches to understanding the pathology and developing new therapeutics. Our central hypothesis is that lack of detoxication of endogenous or xenobiotic amines underlies the pathological condition of some CNS diseases. The human flavin-containing monooxygenase (FMO) is one of the major human enzyme systems that contribute to the detoxication of endogenous, environmental and dietary nitrogen-containing substances. The overall goal of our work is to understand the details of FMO-mediated N-oxygenation of amines and hydroxylamines. Accumulation of hydroxylamines in the CNS may lead to cytotoxicity or apoptosis. To test this, fundamental information about human brain FMO N-oxygenation is required. The overall goal will be accomplished by addressing five Specific Aims including:
Aim 1 : cDNA-express the major forms of human brain FMO;
Aim 2 : Chemically synthesize amine metabolites of human brain FMO;
Aim 3 : Determine the kinetics and mechanism of human brain FMO amine N-oxygenation;
Aim 4 : Test the effects of human brain FMO amine metabolites on neuronal cell function including cytotoxicity and apoptosis, and Aim 5: Investigate the mechanism of amine metabolites on human neurotransmitter function. The significance is that fundamental biochemical information will result in new insight about the way endogenous and xenobiotic and dietary amines are metabolized in human brain. Such fundamental information will be useful in the development of safer drugs, the prevention of adverse drug reactions and the protection of humans from disease.
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