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READY FOR THE FUTURE Biodefense Preparations By Russ Willcutt In November 2003, the National Institute of Allergy and Infectious Diseases (NIAID) announced plans to build two national and nine regional level-three biocontainment laboratories and issued a call for proposals. Of the more than 30 responses that NIAID received, UAB was among those funded, receiving a $15.9 million grant. “The grant was structured so that it required a one-to-three match, however, so the university needed to secure about $5 million in matching funds,” says Richard Marchase, Ph.D., senior associate dean for biomedical research at UAB and principal investigator on the grant. “About a month later, in response to a request by President Garrison and Chancellor Portera, Governor Riley pledged the money from the state, which will allow us to build this $21 million facility.” Sites are being evaluated on and near campus for the 40,000-square-foot facility, which will be known as the Southeast Biosafety Laboratory Alabama Birmingham (SEBLAB). Marchase says it should be operational by early 2007. “We expect to continue our anthrax-related research, as well as research to develop diagnostic screening methods and vaccines for anthrax, West Nile virus, and the flu,” says Marchase, adding that investigators from throughout the region will have access to the facility. “In writing the proposal, we made the case that we have an exceptional group of investigators here at UAB, and that we’re one of the strongest universities in the country in terms of our potential to understand and defend ourselves against these deadly agents.” Those strengths will be bolstered by a consortium of universities known as the Southeastern Regional Center of Excellence for Emerging Infections and Biodefense (SERCEB). According to Richard Whitley, M.D., a founding member of the National Institutes of Health-funded organization, “This is a founding group of six universities—indeed, all academic medical centers in our region—that will work together to develop vaccines, drugs, and diagnostic West Nile virus under the microscope. tests against emerging infections such as West Nile virus, among many others. We will also be conducting research into organisms such as smallpox that could be used in bioterrorist attacks.” UAB’s partners in this effort are Duke University, Emory University, the University of Florida, the University of North Carolina, and Vanderbilt University. Taking the results from research conducted through the NIAID Collaborative Antiviral Study Group (CASG) contract—which was recently refunded for $34 million over a seven-year period, with Whitley as principal investigator—scientists at UAB, Southern Research Institute, and other SERCEB member institutions will work to develop antiviral drugs to combat emerging infections such as West Nile virus and, eventually, even severe acute respiratory syndrome (SARS). “We’re especially interested in the orthopox family, which includes smallpox and monkeypox,” says Whitley. “Just to give you an example of what this collaboration is allowing us to do here on campus, we have Earl Kern and Mark Pritchard doing antiviral drug screening in the Division of Infectious Diseases at Children’s, and Ming Luo and Larry DeLucas at the Center for Biophysical Sciences and Engineering studying the 3-D structure of the enzymes necessary for these viruses to replicate. David Chaplin examined innate host immune responses to biothreat organisms, and Jack Secrist, Tom Voss, and colleagues at Southern Research Institute are synthesizing drugs based on these structures that will attack smallpox from a completely different angle, as well as providing animal models to study the efficacy of these drugs. So it’s this huge, multidisciplinary effort, with the same shared goal. “Our hope is that SERCEB and SEBLAB will help unite scientists from all across campus, and the region, with each contributing their particular expertise,” says Whitley. “Because, to me, that’s one of the most important characteristics of UAB—we truly are an institution without walls.” Searching for a Diabetes Cure ISLET CELL TRANSPLANTATION By Laura Freeman As anyone suffering from the complications of type I diabetes can attest, insulin is far from a cure. Even if patients manage to avoid blindness and amputation of extremities—for which they are at high risk—they are still more likely to die prematurely from heart or kidney disease than nondiabetics. While transplants have been changing the lives of patients with other organ failures for years, until recently the sensitivity of pancreatic islet cells to immunosuppressive drugs has limited the effort to bring that hope to diabetics. However, Devin Eckhoff, M.D., and his team are working to change that situation. In April, they performed the first islet-cell transplant in Alabama, using a technique pioneered in Canada that employed a less-toxic combination of immunosuppressive drugs and reversed diabetes in 85 percent of patients. After two years, the success rate for the University of Alberta at Edmonton program continues to be an impressive 75 percent. 14 A LIFE WITHOUT INSULIN “Our ultimate goal is to help patients live without insulin or immunosuppressive drugs,” says Eckhoff, division director of transplantation surgery. “The transplant procedure injects islet cells through a catheter. The cells lodge in the liver and begin producing insulin.” The team, which includes Carlton Young, M.D., overseeing clinical aspects, and Juan Contreras, M.D., heading up the lab, hopes to take what they learn in duplicating the Edmonton study and make modifications in the second stage of their program. “We’ll be working on finding new approaches to improve the survival of islet cells,” adds Eckhoff. “We want to transplant more viable cells and learn how to help more of them survive without damage or rejection.” Since only about half of the new islet cells typically make the transition to become a functioning transplant, living donors are not an option at this point; they would be unable to contribute sufficient numbers of islet cells to free a diabetic from the need for insulin. However, the patient and donor have to share only the same blood type, which improves the odds of finding a compatible donor organ. Close tissue matching is not necessary and perhaps not even desirable, since a too-close match could make the new islet cells vulnerable to the same type of attack that damaged the patient’s pancreas.
IN PRAISE OF WINE The Great Protector By Laura Freeman “To your health!” That traditional toast, long raised over glasses of wine, is proving to be prophetic. Recent major studies have shown a consensus that light to moderate consumption of alcohol (one to four drinks daily for men, one to two for women), particularly red wine, can help prevent coronary-artery disease and heart attacks. The big question that remains centers on the mechanisms behind wine’s preventative benefits. UASOM professor Francois Booyse, Ph.D., and his team of 17 researchers are working on a study funded by a $7.6 million, five-year grant from the National Heart, Lung and Blood Institute to find the answer—or in this case, the answers. Multiple components in wine appear to work together to attack heart disease on several fronts simultaneously. In addition to helping prevent arteriosclerosis and lowering blood pressure when consumed in moderation, elements within wine seem to help reduce thrombic risks that could lead to a heart attack. “Our program specifically focuses on studies related to the effects of low to moderate levels of alcohol and polyphenols on the mechanisms of fibrinolysis, a normal ongoing process that results in the removal of small blood clots, and vasoreactivity,” says Booyse. “Both alcohol and various individual polyphenols inhibit the activity/production of a number of specific enzymes as well as fibrinogen, all directly involved in and responsible for reduced coagulation or clotting. In addition, alcohol and polyphenols will simultaneously increase the production of various enzymes involved in clot lysis, further reducing the overall risk of clot formation and heart attacks.” Alcohol and polyphenols have also been shown to increase plasma High-Density Lipoprotein (HDL) cholesterol, which many investigators believe helps protect the cardiovascular system through a process known as reverse cholesterol transport. “Increased plasma HDL will bind more cholesterol and reduce the level of the Why wine? Fermentation raises the number of beneficial polyphenols— giving it an edge over grape juice. lipoprotein-cholesterol pool in the vessel wall and its deleterious effects in vascular tissue and cells,” notes Booyse. Would a glass of grape juice with breakfast every morning have the same beneficial effects? Probably not. Although both juice and wine may begin with grapes from the same vineyard, chemical changes happen along the way. “Polyphenol composition, content, and often structure are modified and altered during fermentation,” Booyse explains. “Grape juice contains lower levels and a different composition of polyphenols.” The long-term goal of studying the heart benefits of wine is to gain insights that can be used in developing better drugs and therapeutic strategies to help both wine drinkers and nondrinkers avoid heart disease and live longer, healthier lives. Working with animal models, mouse-derived blood vessels and hearts, and cultured endothelial cells and cardiomyocytes, the UAB team draws on the talents and expertise of researchers from multiple disciplines. In addition to Booyse, who is a professor of medicine and director of the Molecular Cardiology Research Program, the principal investigators and project leaders include Edlue Tabengwa, MSC, and Hernan E. Grenett, Ph.D., of the Department of Medicine; Dale A. Parks, Ph.D., of the Department of Anesthesiology; and Victor Darley-Usmar, Ph.D., of the Department of Pathology. Twelve other researchers include faculty and co-investigators from the departments of Genetics, Pathobiology, Pharmacology and Toxicology, and Physiology and Biophysics. Unlike fine wines, which may require years of aging, the first fruits of this study are already being shared. The team is contributing its insights and conclusions on a continual basis, typically publishing 10–12 papers and 15–20 abstracts per year. When the study’s final results are gathered, learning more about how wine helps to save hearts may teach us something worth celebrating with a sip of champagne—or better yet, a hearty burgundy or merlot. IMPROVING IMMUNOSUPPRESSION UAB transplant immunologist Judith Thomas, Ph.D., has been working with primates with diabetes to improve their tolerance to immunosuppressive drugs and to reduce their need for insulin. “We’re hoping to build on her success,” says Eckhoff. “Data from her research is helping the transplant program select immunosuppressive drugs that are more effective and less damaging to islet cells.” There is a possibility UAB’s genetic research could make a contribution down the line. “Perhaps we’ll eventually be able to modify islet cells from pigs and make transplants available to more diabetics so they won’t Fighting a killer: This April, a team led by Devin Eckhoff (seated), and colleagues Juan Contreras and Carlton Young, perfomed the first islet cell transplant procedure in Alabama. Their efforts may one day give type I diabetics a life without insulin injections. 15 have to depend on insulin injections,” Eckhoff adds. Meanwhile, the team is still evaluating and selecting patients for the first stage of the study. They will continue to perform transplants as often as donor islets become available. “For now, our selection criteria include making sure a transplant could be a net benefit for any patients we choose,” says Eckhoff. “Rather than selecting those whose diabetes is well controlled with insulin, we’ll be looking at patients who are having complications from diabetes or difficulty maintaining blood-sugar levels due to hypoglycemic unawareness or other factors. “The potential for helping patients with type II diabetes is limited, since their problem is insulin resistance rather than lack of insulin. Transplants, however, could eventually be part of an approach to help those whose islet cells have been exhausted,” he adds. For Eckhoff and other UAB researchers—and the one million insulin-dependent diabetics in America—developing a cure to end diabetes would be sweet success indeed.
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