| Paul Ernsberger graduated from Macalester College in St. Paul, Minnesota in 1978, and in 1984 earned his Ph.D. in Neuroscience from the Department of Pharmacology at Northwestern University in Chicago, with a thesis entitled:"Neural mediation of genetic and nutritional effects on blood pressure: Role of adrenergic receptor regulation in kidney, brain, and heart." He received his postdoctoral training at the Laboratory of Neurobiology of Cornell University Medical College in New York City, and then continued at Cornell as an Instructor in 1987 and an Assistant Professor in 1988. Subsequently, in 1989, he came to CWRU as an Assistant Professor of Medicine, Pharmacology and Neuroscience, and advanced to Associate Professor in 1995. | ||
| In January 1998, his primary affiliation was changed to the Department of Nutrition. His honors include National Science Foundation Fellowship(1981), M. Robert Gallop Fellowship of the New York Heart Association (1984), Young Investigator Award from the Eastern Hypertension Society (1987), FIRST award from the National Institutes of Health (1990), DuPont/Merck FASEB Travel Award (1992), Member of the Subcommittee on the Imidazoline Receptor of the Committee on Receptor Nomenclature and Drug Classification, International Union of Pharmacological Sciences (1994), Member of the International Advisory Board to the Third International Symposium on Imidazoline Receptors (1997). |
| Our laboratory has two
major overlapping foci. One is centered around genetic obesity and
the role of nutrition in cardiovascular disease. The other focus is
on the role of lipids in the signaling pathways of a novel receptor
protein expressed in the brain, the I1-imidazoline receptor. At any
given time, tens of millions of Americans are on weight loss diets.
Most will lose weight, but 95% or more will eventually gain the weight
back and some will gain back more than they lost. Cycles of weight
loss and regain can be harmful. Epidemiological studies show higher
than expected rates of heart attacks and deaths among "yo-yo
dieters". Why does losing and regaining weight seem to raise
the risk of cardiovascular disease? What is the influence of diet
composition during the weight loss and relapse phases? Our studies are directed towards answering this question by using our own genetic animal model, the SHROB rat, which is both obese and has high blood pressure. These rats have a spontaneous gene knockout for the receptor for leptin, a hormone made by fat cells that regulates appetite and metabolism. When SHROB rats are made to lose and regain weight, their blood pressure soar even higher, they become even fatter, and heart and kidney disorders are exacerbated. Future studies will unravel the hormones and neurotransmitters involved in this weight cycling syndrome, identify diets that ameliorate the syndrome, discover genes that can modify the risk factors, and extend these studies to human patients. Additional studies will seek drug therapies that correct abnormalities in obesity, diabetes and high blood pressure. See Figure 1 below ---l1-imidazoline receptor signaling pathway (From Ernsberger, et al., 1997.) 
A hypothetical model for the signaling pathways of I1-imidazoline receptors. The receptor is depicted as resembling a cytokine-receptor, because its signaling pathways are characteristic of cytokine receptors. Agonists, such as moxonidine or rilmenidine, when bound to the I1-imidazoline receptor activate of PC-PLC, possibly through coupling to an unidentified G-protein (Gx). The plasma membrane enzyme PC-PLC, in turn, uses phosphatidylcholine as a substrate and generates diglyceride and phosphocholine. Diglyceride then activates protein kinase C (PKC). The I1-imidazoline receptor is itself a substrate for protein kinase C, leading to an increase in binding affinity after phosphorylation by PKC. Stimulation of the I1-receptor elicits release of arachidonic acid and its metabolite prostaglandin E2 into the extracellular medium. Other eicosanoid metabolites of arachidonic acid metabolites are likely to be produced in response to I1-receptor stimulation. The enzymatic pathway responsible for the liberation of arachidonic acid in response to activation of I1-imidazoline receptors does not involve phospholipase A2, which directly liberates arachidonic acid. A likely alternative is diglyceride lipase, which can liberate arachidonic acid from diglycerides. Also indicated are the inhibitors D609, blocking PC-PLC, and efaroxan and BDF-6143, competitive receptor antagonists. A promising new avenue for therapy of both high blood pressure and diabetes is a class of drugs acting on I1-imidazoline receptors. When SHROB are treated with imidazoline drugs, it not only lowers blood pressure, but it also improves glucose tolerance, enhances signaling through the insulin receptor, and treats their heart and kidney disorders. In order to understand how this operates at the cellular level, we are studying cell signaling pathways coupled to I1-imidazoline receptors (see illustration). So far, we have found that these receptors trigger production of two lipid second messengers, diacylglyceride and arachionic acid. Diacylglyceride activates protein kinase C, a key regulatory enzyme. Arachidonic acid is the parent compound to the prostaglandins and the eicosanoids. In the nervous system, these molecules might serve to transmit information between neuronal cells. Future studies will extend our understanding of this pathway and how it might regulate gene expression, and discern its interaction with signaling pathways for insulin and other metabolic hormones.
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| Contact Dr. Paul
Ernsberger at (216) 368 - 4738 or by email at pre@cwru.edu |
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