University of Washington
J-661F Health Sciences Building
Biochemistry, Box 357370
Seattle, WA 98195
Phone: (206) 543-6064
Phone: (206) 543-6090
Dr. Palmiter's group has two research interests. One area involves the role of catecholamines in the development and function of the mammalian nervous system. By inactivating the dopamine b-hydroxylase (DBH) gene, mice were created that cannot synthesize norepinephrine or epinephrine. They die, apparently due to cardiovascular failure, between day 11 and 13 of gestation. However, they can be rescued to birth by providing the mothers with b-agonists or dihydroxyphenylserine, a norepineprine precursor. After birth they do remarkably well as long as they are not stressed.
The Palmiter lab is in the process of studying their physiological, metabolic and behavior deficits. The Palmiter lab has also made mice in which the dopaminergic neurons cannot make dopamine, but norepinephrine-producing neurons are normal, by inactivating the tyrosine hydroxylase (TH) gene and then restoring TH function in noradrenergic cells. These mice are born at normal frequency and begin to suckle and grow normally but after about 2 weeks they become hypoactive and stop feeding. They can be rescued to adulthood by daily administration of L-dopa, the product of the TH gene. The effect of dopamine deficiency on locomotion was expected; however, the profound effect on feeding behavior was not anticipated.
These mice will provide ideal recipients of various gene therapy approaches. One approach will be to introduce the TH gene into specific neurons to determine which neurons control feeding and locomotor behaviors, the other involves systemic production of L-dopa to determine whether all the deficits can be reversed by chronic supply of L-dopa. Another project that is just beginning involves the role of neuropeptide Y, which is coexpressed with catecholamines in the sympathetic nervous system, in various physiological processes.
The other research interest involves the analysis of zinc homeostatsis in mice and cultured cells. Transporters involved in the influx and efflux of zinc from cells are being cloned and characterized. Other members of this family are involved in transport of zinc into intracellular vesicles. For example, zinc is stored in synaptic vesicles of certain neurons and may function as a neuromodulator. A central question relates to the molecular mechanism by which cells "sense" the concentration of intracellular zinc and regulate its abundance. One aspect of this regulation involves the transcriptional control of genes including the metallothionein genes. Various metallothionein genes have been disrupted by gene targeting as a means of discerning the function of these ubiquitous metal-binding proteins.
Investigator: Dr. Palmiter is a Professor of Biochemistry and Investigator of the Howard Hughes Medical Institute. He is also a member of the National Academy of Sciences.