TODAY news - August 28, 2003 - School of Medicine news

Thursday, August 28, 2003 TODAY

School of Medicine news

School of Medicine Professor receives $1 million NIH grant

Dr. Duerksen-Hughes’ research team (from left): Back row, Adrian Chen; Valery Filippov, research associate; and Carlin Williams. Front row, Theodore Garnett; Penelope Duerksen-Hughes, PhD, principle investigator; Kurt Meyer; Andrea Korsich; Maria Filippova, research associate; and Lindsey Parkhurst.

The National Cancer Institute of the National Institutes of Health granted Penelope Duerksen-Hughes, PhD, associate professor of biochemistry at Loma Linda University School of Medicine, $1 million over five years to study the high risk human papillomavirus–16 (HPV-16), which is the most frequent cause of cervical cancer deaths in the United States. Dr. Duerksen-Hughes and her team will examine how the virus affects the host system.

“ You can look at it like an arms race,” says Dr. Duerksen-Hughes. Viruses force a cell to make all the small parts of itself, while the host organism activates systems designed to kill these infected cells. The virus then adapts to bypass these new defenses, and the two are constantly involved in an escalating race for survival.

Specifically, Dr. Duerksen-Hughes and her team will be looking at the E6 protein that the HPV-16 produces. This protein prevents the host from killing infected cells by engaging receptors on the infected cell and blocking the action of the host’s fleet of killing cells.

These killing cells produce a protein called TNF. Normally, TNF should cause an infected cell to die, but it is ineffective for cells making E6.

“ We’d like to know what parts of the E-6 protein bind to the TNF receptors and how widespread this tactic is,” says Dr. Duerksen-Hughes.

“ The ultimate goal of this grant is to understand the molecules and what they do,” says Dr. Duerksen-Hughes. By the end of the five-year grant she hopes to actually start looking at inhibiters of E6. This is all part of a long-term project she has been working on since 1994, when she first became interested in the subject. Dr. Duerksen-Hughes will be beginning her fourth year at Loma Linda University in September, the same time the first grant check arrives from the NIH. Before coming to LLU, she was researching the topic at Georgia State University in Atlanta, Georgia.

The NIH funds roughly 20 percent of all the grant applications it receives each year. Having her grant request funded is a confirmation and validation from peers at other institutes who recognize her ideas as worthy of further research.

“ It means more people and more money,” says Dr. Duerksen-Hughes. “It’s exciting, and I hope we can take it to the next level.”

On a practical level, it means she can make more rapid progress and plan more efficiently for the next five years.

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School of Medicine professors receive diabetes research grant

The international research team is composed of William Langridge, PhD (center, leaning over), professor of biochemistry, School of Medicine, and principle investigator of the study; and (from left) Istvan Fodor, PhD, professor of microbiology, School of Medicine, and co-investigator of the study; Bela Denes, PhD, visiting scientist from Hungary; Jie Yu, PhD, postdoctoral fellow; and Valentina Krausova, PhD, visiting scientist from Russia.

Children and young adults, who are most at risk for developing type 1 diabetes, have hope for the future. Principle investigator William Langridge, PhD, professor of biochemistry, School of Medicine, and co-principle investigator Istvan Fodor, PhD, professor of microbiology, School of Medicine, are recipients of one of sixteen National Institutes of Health (NIH) R21 grants to support “innovative partnerships in type 1 diabetes research” throughout the United States.

Their partnership for development and preclinical evaluation of a “Vaccinia Virus Vaccine for Type 1 Diabetes” in the Center for Molecular Biology and Gene Therapy is aimed at preventing the onset of type 1 diabetes disease symptoms. The research grant will provide $820,000 throughout the next two years.

Type 1 diabetes develops when the body’s immune system destroys the pancreatic islet beta cells that make the hormone, insulin, which regulates blood glucose uptake into cells of the body. This form of diabetes has a genetic predisposition, is stimulated by environmental factors, and usually strikes children and young adults. As a result, those who have diabetes need to measure blood sugar levels and inject insulin several times a day to survive.

“ The goal of the study is to use vaccinia virus to enhance the targeting of pancreatic islet autoantigens (insulin and glutamic acid decarboxylase) to the mucosal immune system to elicit a stronger immunotolerization response,” states Dr. Langridge.

The process of immunotolerization has been shown to suppress destruction of the islet insulin-producing beta cells in non-obese diabetic (NOD) mice, a mouse model for the human form of the disease.

Dr. Langridge’s research team was the first in the United States to report immunotolerization of NOD mice by feeding them potatoes from plants genetically engineered to make small amounts of the insulin and glutamic acid decarboxyalse (GAD) islet autoantigens. Although the emerging field of plant vaccines has the potential to one day revolutionize vaccination programs worldwide, a more conventional diabetes vaccine for immunotolerization might benefit many people at risk for type 1 diabetes sooner.

To strengthen the immunotolerization approach to diabetes prevention, the Langridge and Fodor laboratories will work together to genetically engineer a vaccinia virus vaccine strain to make the insulin and GAD diabetes autoantigens. They will also test the vaccine for suppression of diabetes symptoms in NOD mice.

The efficacy of virus- mediated tolerance for prevention of type 1 diabetes in vivo will be evaluated in prediabetic NOD mice. Currently, the team is constructing a series of recombinant vaccinia viruses expressing different versions of the two islet autoantigens. The recombinant vaccinia viruses will be purified and characterized in cultured cells, and will then be applied in a crucial tolerization experiment in NOD mice.

“ The results of these experiments,” says Dr. Fodor, “will increase our understanding of the immunological mechanisms underlying vaccinia virus mediated immunotolerization against type 1 diabetes for the long-term goal of generating safer, more effective, and inexpensive mucosal vaccines for protection against this devastating life-long form of diabetes.”

Vaccinia virus has also been used for smallpox vaccination. Dr. Fodor’s research team has reported encouraging preclinical results with vaccinia virus cancer gene therapy, in which vaccinia virus production of anti-cancer proteins in tumors suppress their growth.

If the preliminary results of the vaccine studies in NOD mice are encouraging, Drs. Langridge and Fodor will complete the required preclinical studies prior to clinical evaluation of the vaccine.

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Thursday, August 28, 2003 TODAY