December 18, 1998

Researcher’s protein work earns federal MERIT grant

Researcher's protein work earns federal MERIT grant

A VUMC researcher's study of how a certain protein affects red blood cells has earned him a Method to Extend Research in Time (MERIT) grant from the National Institutes of Health (NIH).

Albert H. Beth, Ph.D., professor of Molecular Physiology and Biophysics, received the coveted five-year grant for his work on the structure of a protein critical for red cell function

He becomes the ninth VUMC researcher to receive a MERIT grant, awarded by the NIH to investigators whose research appears to have a good chance at producing results that will impact human health. The grants provide seven years of continuous funding without recompetition.

Other MERIT awardees are Alan D. Cherrington, Ph.D., professor and chair of Molecular Physiology and Biophysics; Lee E. Limbird, Ph.D., associate vice chancellor for Research; Conrad Wagner, Ph.D., professor of Biochemistry; Michael R. Waterman, Ph.D., Natalie Overall Warren distinguished professor and chair of Biochemistry; Dr. Doyle G. Graham, professor and chair of Pathology; Elaine Sanders-Bush, Ph.D., professor of Pharmacology; Dr. Fridolin Sulser, professor of Psychiatry and Pharmacology; and Dr. Daryl K. Granner, Joe C. Davis Professor of Biomedical Science and director of the Vanderbilt Diabetes Center.

A MERIT Award is a vote of confidence from the NIH based on past productivity and impact on a field," said Lee E. Limbird, associate vice chancellor for Research. "What is most important is that extended period of probably funding ‹ it invites and accomplished scientist to take bold risks, and I would say that all of us would agree that those risks yield unexpected findings we might never have had the opportunity to make."

Beth's research focuses on the structure of a protein in the membrane of red cells, called band 3 protein, and how it changes when an ion passes through the cell membrane.

"One of the major questions left in Cell Biology is how cells communicate with the outside world. These proteins are one of the ways that that communication takes place."

Band-3 has two functions that make it unique. First, it is responsible for the exchange of chloride and bicarbonate across membranes, which is how red cells carry carbon dioxide back to the lungs for exchange with oxygen.

Secondly, there is another piece of the protein that connects with cell membranes. Defects in that connection can cause a cell to be fragile or have abnormal shapes.

Continued research into the mechanics of band-3 may reveal a way to treat a class of disease called hemolytic anemias, in which cells burst open when they travel through the microcirculation.

At a more fundamental level, these studies give clues about how nature has selected a complex set of membrane proteins and built them into an architecture that is both stable and flexible, providing the stability required by a cell membrane, which must withstand extreme shearing forces, as they pass through capillaries of microscopic diameters.

VUMC's other MERIT grant holders are pursuing various fields of study.

o Cherrington's research focuses on diabetes, but could also lead to new understandings of how nutrition can impact on recovery following injury or patients with weight disorders like obesity.

Cherrington initially focused his work on glucagon, which is secreted from the pancreas. His work has helped establish glucagon as being a critical partner with insulin in regulating the level of blood glucose.

o Since joining VUMC's faculty, the focus of Limbird's lab has been on the one subset of cell surface receptors for adrenaline and nonadrenaline known as alpha2 adrenic receptors.

These receptors are found throughout the body and can serve a number of different functions, from monitoring free-floating adrenaline in the bloodstream to serving as a neurotransmitter between nerve cells. Studies funded by the MERIT Award allowed Limbird and her colleagues to reveal the role a particular receptor plays in lowering blood pressure, suppressing pain, mediating sedation and anesthesia, and suppressing epileptogenesis. In fact, unexpected findings suggest a new strategy for developing antiepileptogenic drugs.

o Wagner's research has been aimed at understanding the role of single-carbon compounds in cellular mechanisms.

Folic acid, which has garnered attention for its role in neural tube defects in infants, has been a target of study in Wagner's lab for many years. Divining the mechanisms by which these single-carbon compounds impact gene activation in cells may lead to greater awareness of cellular function and action.

o Waterman is studying the roles of proteins found in the endoplasmic reticulum and the mitochondrion of steroidogenic tissues (gonads and adrenal) which participate in steroid hormone biosynthesis. Previously it was difficult to study these enzymes because they are membrane-bound and difficult to purify.

The mitochondrial enzyme under study (cholesterol side chain cleavage P450) is involved in the conversion of cholesterol to pregnenolone, which is a key intermediate in production of all steroid hormones including androgens, which stimulate the development of male sex organs, and estrogens, which control female sexual development.

o Graham is studying the effects of inhalation of hexane-based glue, either as a result of chronic industrial exposure or purposeful inhalation. Using nuclear magnetic resonance spectroscopy and other techniques, Graham has shown that exposure leads to accumulations of neurofilaments and the degeneration of the distal axon.

o Sanders-Bush is studying spontaneously active seratonin receptors, which activate nerve processes even in the absence of the neurotransmitter, serotonin, or drugs that are meant to increase serotonin activity. These findings may have profound implications for treating certain psychiatric diseases by designing drugs that suppress the ongoing receptor activation without preventing receptor response to serotonin, when ultimately released into the synapse.

o Sulser's research has been focused on trying to understand the inter-relationship of serotonin and norepinephrin functions, especially how they interdependently modify gene expression in the brain. His clinical efforts focus on the mechanism of action for antianxiety, antidepressant, and antipsychotic drugs.

o Granner's research focuses on the phosphoenolpyruvate carboxykinase (PEPCK) gene, a complete analysis of which could unlock the metabolic mechanisms of glucose production in the liver.