Randy Strong, Ph.D.
Professor
Department of Pharmacology, UTHSCSA

(210) 567-4760
strong@uthscsa.edu

Our research is directed at mechanisms involved in regulation of catecholamine levels and how these mechanisms are altered in aging and disease. The catecholamines dopamine, noradrenaline and adrenaline are involved in diseases such as schizophrenia, depression, hypertension and Parkinson's disease. One project is to determine how glucocorticoids interact with neurotransmitters in controlling transcription of the gene coding for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. We were the first to identify a glucocorticoid responsive element in the promoter region of the TH gene. We have found that activation of the cAMP intracellular signaling pathway inhibits the effects of glucocorticoids on transcription of TH by a novel pathway requiring MAP kinase but not the cAMP-dependent protein kinase (PKA). We are currently investigating the other components of that pathway. This mechanism may serve to prevent the production of potentially toxic levels of catecholamines when the hypothalamic-pituitary adrenal axis and the sympathetic nervous system are activated simultaneously.

A second project is to study mechanisms altering TH gene expression in the peripheral nervous systems during aging. We have found that age-related alterations in TH gene expression occur at the level of TH mRNA stability. We are investigating the role of signaling pathways and TH mRNA proteins in regulating stability of the TH transcript. A third project is concerned with the pathogenesis of Parkinson's disease. Our data indicate that the aldehyde metabolite of dopamine (DOPAL) is a specific neurotoxin for neurons that use dopamine as a neurotransmitter, the same neurons that are affected in Parkinson's disease. Our studies show DOPAL is elevated in the brains of those who died with Parkinson's disease, and we are deciphering the mechanism for this elevation, focusing on the mitochondrial aldehyde dehydrogenase enzyme (ALDH2). We have developed the first knockout mouse with a targeted deletion of the ALDH2 gene to determine the role of this enzyme in regulating DOPAL levels.

PUBLICATIONS:
Corbitt,J., Hagerty,T., Fernandez,E., Morgan, W.W. and Strong, R. Transcriptional and posttranscriptional regulation of tyrosine hydroxyalse messeneger RNA in PC12 cells during persistent stimulation by VIP and PACAP38: Differential regulation by protein kinase A- and protein kinase C-dependent pathways. Neuropep. 36, 34-45, 2002.

Dong L.Q., Ramos F.J., Wick M.J., Lim M.A., Guo Z., Strong R., Richardson A. and Liu F. Cloning and characterization of a testis and brain-specific isoform of mouse -phosphoinositide-dependent protein kinase-1, mPDK-1. Biochem. Biophys. Res. Comm. 294, 136-144, 2002.

Hagerty T., Fernandez E., Lynch K., Wang S. S., Morgan W. W., and Strong R. Interaction of a glucocorticoid-responsive element with regulatory sequences in the promoter region of the mouse tyrosine hydroxylase gene. J Neurochem 78, 1379-1388, 2001.