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Unlap_Tino


M. Tino Unlap, Ph.D.

Associate Professor, Department of Clinical Laboratory Sciences


Publications

Contact Information
SHPB 450
(205) 934-7382

Email: unlap@uab.edu


RESEARCH DESCRIPTION

     My laboratory is studying the role that oxidative stress plays in the pathogenesis of hypertension.  Studies have shown that the adverse effects of oxidative stress are mediated through reactive oxygen species which include  superoxide anion (O2.-), hydrogen peroxide (H2O2), hydroxyl radical (OH.-) and peroxynitrite (ONOO-), which exert a variety of effects in the renal vasculature including dysregulation of cytosolic calcium homeostasis, elevation of intracellular Na+ and Ca2+ and induction of membrane depolarization.  Because the Na+/Ca2+ exchanger plays a crucial role in maintaining cytosolic calcium homeostasis, we hypothesize that elevation of intracellular Na+ levels which leads to membrane depolarization and increased Ca2+ influx through the Na+/Ca2+ exchanger, an effect which is significantly greater in renal vasculature of the Salt Sensitive Dahl rat. Studies in my laboratory is are testing this hypothesis in preglomerualr vascular smooth muscle cells of Salt Sensitive and Salt Resistant Dahl rats and, for mechanistic studies, in Opossum kidney (OK) cells stably expressing RiNCX and SfNCX,  two Na+/Ca2+ exchanger isoforms that we previously cloned from renal vasculatures of the Salt Resistant and Salt Sensitive Dahl rats, respectively. 

     The studies are as follows: Study 1) to demonstrate that oxidative stress induces an elevation in intracellular Na+ either through activation of Na+ channels and/or the Na+/H+ exchanger or through inhibition of the Na+/K+-ATPase which elevate intracellular Na, study 2) to demonstrate that oxidative stress-induced intracellular Na+ elevation leads to membrane depolarization, study 3) to demonstrate that oxidative stress-induced membrane depolarization causes Ca2+ influx through the  Na+/Ca2+ exchanger in exchange for Na+ (reverse mode), and study 4) to demonstrate that differences in susceptibilities of preglomerular vascular smooth muscle cells to oxidative stress-induced cytosolic Ca2+ dysregulation is mediated through amino acid differences between the two Na+/Ca2+ exchanger isoforms.  Understanding the role that the Na+/Ca2+ exchanger plays in mediating the adverse effects of oxidative stress on Na+ channels, the Na+/H+ exchanger and the Na+/K+-ATPase in the pathogenesis of hypertension provides a potential single target for the treatment of this debilitating disease. 

     The above figure illustrates the relationship between 5 transmembrane proteins that we are currently studying in the lab.  We cloned the Na+/Ca2+ exchanger from the renal vasculature of salt sensitive and salt resistant Dahl rats and found that these rats express isoforms that differ by one amino acid at residue 219 which is isoleucine in the salt resistant isoform but is phenylalanine in the salt sensitive isoform.  Our preliminary studies showed that the single amino acid difference predisposes the salt sensitive Na+/Ca2+ exchanger isoform to an oxidative stress-induced switch from Ca2+ extrusion mode to Ca2+ influx mode which can lead to abnormal increase in cytosolic Ca2+ concentration, increased vascular tone and hypertension.  The four studies that are currently underway in the lab examine the effect of oxidative stress on the activities of Na channels, N/H exchangers, and the Na/K-ATPase in initiating membrane depolarization and the role that membrane depolarization might have on Ca2+ influx through the Na+/Ca2+ exchanger.   Understanding this is critical to our understanding of the pathogenesis of salt sensitive hypertension and will assist us in the development of better diagnostic and treatment paradigms.

BIOGRAPHY

     Dr. Tino Unlap is an Associate Professor in the Department of Clinical Laboratory Services.  Dr. Unlap received his B.S. from Western Kentucky University, Bowling Green, KY in 1981 in Chemistry, and he also completed his M.S. from Western Kentucky University in 1983 in Biology.  He moved to Manhattan, KS and completed his Ph.D. in 1989 in Biochemistry and Molecular Biology.  Dr. Unlap completed his postdoctoral studies at UAB in 1992 in Hematology and Oncology.  He joined he UAB faculty in 1997.