The GCRC Career Development Program’s Clinical Associate Physician program and Minority Clinical Associate Physician (MCAP) support M.D. researchers who will work on clinically oriented projects ranging from studies on whole humans down to tissues and cells. The awards are for three years with stipends of $50,000, $55,000 and $60,000 (plus fringe). In addition, there is an allowance of $7,500 per year which can be used to support the research effort, for travel, and etc.

CAP grants submitted to the National Institutes of Health (NIH) have a funding rate of nearly 50 percent. “Many young investigators need the kind of chance the CAP and MCAP funding offers, said L. Lyndon Key, M.D. As program director of MUSC’s General Clinical Research Center (GCRC), Key understands the difficulty young clinical researchers would face if they had to compete with seasoned NIH-supported investigators for limited federal funding. “With these programs they’re competing with their peers.”

The CAP and MCAP programs grant research funding to awardees who do not have nor have had NIH funding for an individual research project. Also, they must be within five years of having completed their fellowship. To apply, each candidate must design a clinical research project which will be carried out with a clinical/research mentor (M.D. is generally required). This project must be endorsed by the GCRC Advisory Committee and the proposal is submitted as a supplement to the GCRC grant. The grantee’s department must commit at least 80 percent of his or her time to carrying out research. Salaries can be supplemented with institutional funds to an appropriate institutional level.

Key said he anticipates an even greater use of GCRC services as more CAP and MCAP grants are awarded. “Fewer patient-based projects are being funded by NIH,” he said, “largely because working with people as research subjects presents problems in controlling variables that can affect data.” He cited different lifestyles, diet, exercise habits, and stress levels as examples of the variables. GCRC services, however, put greater controls on such variables.

“Only clinical research can translate test tube discoveries to a clinical product,” Key said. He explained that discoveries from the lab have to be tested physiologically to see if they are as true in the person as they are in the test tube. “Clinical research is the intermediate step between test tube and therapy.”

CAP grant researchers depend on GCRC

Thielman tests rehydration for HIV patients

Infectious disease specialist Nathan Thielman, M.D., would like to find a more efficient rehydration formula to treat HIV patients suffering from diarrhea, a formula that not only treats symptoms, but repairs intestinal damage as well.

“We’re investigating the efficacy of a glutamine-based oral rehydration formula,” Thielman said, “one that both enhances gut absorption of fluid and promotes repair of cells lining the intestines.”

He explained that epithelial cells lining the intestines form a filter to allow nutrients to pass from food into the blood and be carried to cells throughout the body. They also function as a barrier against intestinal contents that would otherwise harm the body. The epithelial cells of an HIV patient suffering from the severe dehydration of diarrhea often break down or pull away from each other, potentially allowing increased penetration of toxic substances to pass beyond the intestinal wall.

A rehydration formula used extensively by the World Health Organization has saved hundreds of thousands of lives in developing countries throughout the world, Thielman said. Its simple glucose (sugar), sodium chloride (salt), and water composition does an excellent job of carrying needed hydration to dehydrated cells, but it does nothing to knit together epithelial cells that have lost their integrity.

“Glutamine has been shown to provide the energy epithelial cells need to repair themselves,” Thielman said. “We’d like to demonstrate in our investigation that this oral rehydration formula repairs intestinal damage as it treats the symptoms of the diarrhea.” Thielman, who came to MUSC from the University of Virginia in July, uses the resources provided by the General Clinical Research Center. Its availability combined with Charleston’s significant patient population infected with HIV convinced him this was the place to continue his work. He said his study protocol requires patients be hospitalized in the GCRC for seven days of intensive nursing care. Specially trained for the research-sensitive care required by study protocols such as Thielman’s, GCRC nurses collect specimens that GCRC lab technicians analyze, as GCRC dietitians control patients’ food intake.

“My study would be difficult to perform were it not for the skilled staff of the GCRC,” Thielman said. He added that his study is ongoing and still taking referrals from infectious disease practitioners statewide who have patients suffering from HIV-related diarrhea.

Growth factors vital for development of premature infants

Neonatologist Carol Wagner, M.D., calls it a symphony of living cells, an orchestrated growth of a newborn’s gastrointestinal tract in response to growth factors present in human milk. Any disharmony can create problems for a newborn, and that concerns her.

One such concern is gut maturation in prenatal development, especially as it applies to premature and low birthweight infants. “They don’t have complete gut closure,” Wagner said, explaining that they are born with openings between the cells lining their intestines, making cow’s milk-based baby formula, which lack growth factors and hormones, less suitable than human milk for continued gut development after birth.

Wagner’s research seeks to determine the differences in the way a newborn’s gut matures on formula compared to human milk, especially focusing on transforming growth factor (TGF) alpha. Although growth factors are present in vast numbers in human milk, TGF alpha is one that stimulates cells of the intestinal lining to divide.

“It’s present in fetal life, and for premature infants it’s particularly important for catch-up growth,” Wagner said. She said that premature infants fed cow’s milk-based formula instead of human milk have an increased risk of developing necrotizing enterocolitis (NEC). This disease can spread throughout the gut and is particularly difficult to treat. Wagner said NEC kills up to 50 percent of the premature infants who contract it.

“Treatment is not nearly as effective as prevention,” Wagner said, emphasizing the importance of human milk in the development of not only premature infants but full-term infants as well. Human milk is much different than homogenized cow’s milk, Wagner said. Human milk is “compartmentalized.” Its fat molecules are encapsulated with membranes that release their nutrients at specific intervals as the milk passes through the digestive tract. As epithelial cells lining the infant’s gut mature, they become more effective at blocking out molecules in baby formula and later food that would otherwise cause infections and allergies.

“Even the fat content of a mother’s milk changes over time to meet her baby’s needs,” Wagner said, adding that the milk also contains live cells—macrophages and lymphocytes—that produce growth factors in the infant.

Wagner’s research is tracking the development of 130 babies, some of whom are fed formula, to compare their development with others who are fed human milk. The choice of formula or breast milk is the mother’s, as is the time when the baby is weaned from breast feeding to taking formula.

Support for Wagner’s study comes largely from GCRC staff services, including nursing, lab processing, and nutritionists.

“Dr. (Lyndon) Key has been a great help in the scientific development of the project, as has Dr. Susan Baker, who has been a scientific advisor and serves on the science board of the GCRC,” she said. “And I’ve had help from the statistician to figure the numbers of babies to be studied to make this a valid research project, and there’s computer analysis to interpret the data that’s collected.”

GCRC makes atypical diabetes study possible

Steven Willi, M.D., said his presentation at the American Diabetes Association meeting this year raised a few eyebrows when he explained that his study on atypical diabetes in African Americans included children.

“It’s a difficult study to conduct,” Willi said, “and practically impossible without the use of a General Clinical Research Center (GCRC).”

But as a pediatric endocrinologist, Willi is concerned with the progression and diagnosis of an unusual presentation of diabetes found mostly in African Americans. Called atypical diabetes, the disease often presents itself in children as type I, insulin-dependent diabetes. As type I diabetes was once called juvenile onset diabetes, physicians generally assume that when diabetes is diagnosed in a child, the patient will be insulin-dependent for life.

“This is not necessarily so,” Willi said. He explained that his recent findings indicate atypical diabetes can first present as type I, insulin dependent and later not require insulin injections. Instead the diabetes may be controlled with new oral medications that treat a lack of insulin sensitivity in metabolizing sugar in the blood, a condition described as type II diabetes.

The first phase of Willi’s study found that of all African-American children with diabetes, only about half had type I, or were insulin-dependent. Thirty percent of those tested were atypical and the remaining 20 percent had something resembling type II, the type caused by a lack of insulin sensitivity.

“Now we’re trying to identify what characteristics a medical practitioner might look for to identify a child with diabetes who has a potential for not being insulin-dependent,” Willi said. “All of them can be treated with insulin,” he explained, “but some of them can be treated with something other than insulin.”

Willi’s quest is development of a more definite treatment protocol. “I’ve collected DNA samples on all the patients in the study, and now we’re looking for genes in the various diabetes types. There appear to be strong genetic links passing the diabetes from parent to children.” He said that a positive identification of genes associated with type I, type II, and the atypical variety of diabetes could lead to straight-forward testing procedures that readily identify the disease. “Once the genes involved are identified and their function is known, therapies can be designed to correct the problem.”

Willi said that as far as he knows, he’s the only researcher testing children for atypical diabetes. “It’s an intensive investigation, and there’s no way I could have even attempted it without the services of the GCRC.” The center’s integrated nursing, laboratory and nutritional services, which are unparalleled anywhere in the state, make such detailed investigation possible.

“You wouldn’t get these types of studies done anywhere else,” Willi said. “I know. I’ve tried.”