Donal S. O'Leary, Ph.D., professor and director of Cardiovascular Research in the Department of Physiology for the School of Medicine, received the $911,617 grant for his study, “Integrative Cardiovascular Control During Exercise in Hypertension.” The National Heart, Lung and Blood Institute grant comes under the auspices of the American Recovery and Reinvestment Act of 2009, the national economic stimulus package signed into law by President Barack Obama.

Common advice for those with high blood pressure includes monitoring diet and weight, and getting more exercise. For some individuals with hypertension, however, exercise that is too strenuous can over-excite the cardiovascular system, which could lead to an adverse cardiac event. Those select patients can quite literally exercise themselves into a heart attack or death if they engage in strenuous exercise, especially isometric, static exercise like lifting heavy weights or heavy snow shoveling.

“When we examined the literature, we found plenty of information on the good that exercise can do for those with hypertension, but we found almost nothing on the mechanisms mediating the cardiovascular responses to exercise in hypertension,” Dr. O’Leary said.

Dr. O’Leary theorizes that the skeletal muscles of the body, the bigger, load-bearing muscles that contain sensors that send signals to the brain during exercise, may become over-excited in hypertensive patients. Those signals, in turn, lead the brain to regulate the cardiovascular system. For some hypertension suffers, that causes constriction of the arteries and even of the heart, impeding blood flow. This can lead to myocardial ischemia, infarction and other cardiac events such as irregular heart beat.

Using an animal model, Dr. O’Leary’s research team will induce hypertension during exercise in an attempt to discover the cause and signal that over-drive the cardiovascular system, causing arterial constriction. Such a discovery could lead, he explained, to identifying patients who may be susceptible to cardiovascular events during exercise, future drug treatments for such patients and tailored exercise programs to allow these patients to exercise with minimal risk.

While Dr. O’Leary serves as principal investigator, his co-investigators are Javier A. Sala Mercado, M.D., Ph.D., assistant professor of Physiology and the Cardiovascular Research Institute; Tadeusz Scislo, M.D., Ph.D., associate professor of the Department of Physiology; and Noreen Rossi, M.D., professor of Internal Medicine and staff physician at the John D. Dingell VA Medical Center.

His research to date has focused on how the brain controls arterial blood pressure.

“The brain contributes significantly to several cardiovascular-related complications, including hypertension,” Dr. Mueller said. “Most recently, I have become interested in how brain areas that control our blood pressure adapt to regular exercise versus sedentary conditions.”

This research has obvious health-related implications given the beneficial effects of exercise and detrimental effects of physical inactivity on the cardiovascular system, he said.

The researchers discovered that when an Food and Drug Administration-approved cancer treatment typically used to treat cutaneous T-cell lymphoma was administered before a novel experimental antitumor agent -- which works best in breast cancers expressing the estrogen receptor (ER) -- estrogen receptors were reinstated in receptor-negative breast cancer cells so that treatment was also effective in fighting the difficult to treat ER-negative disease.

The research was supervised by Angelika Burger, Ph.D., director of the Translational Research Laboratory at the Karmanos Cancer Institute and professor of the Department of Pharmacology at the School of Medcine. Karri Stark, a doctoral candidate with the School of Medicine, presented the findings.

Researchers have paired vorinostat, known by its pharmaceutical name Zolinza®, with Aminoflavone Prodrug (also known as AFP464) and found that AFP464 and vorinostat work together to inhibit the growth of triple-negative breast cancer cells. “Triple-negative” refers to breast cancer cells that have no estrogen, progesterone or HER2 receptors needed for currently available, targeted anticancer therapies to work effectively.

AFP464 is now in Phase I clinical trials at the Karmanos Cancer Institute, the Mayo Clinic in Minnesota, and other cancer research centers in Paris and Brussels in Europe.

Dr. Burger said the findings offer particular hope to those women battling triple-negative breast cancer.

“We could now find a way to treat every kind of invasive, metastatic breast cancer, the ER-positive and ER-negative types with AFP464,” she said. “The synergism is very impressive. We always knew vorinostat can reprogram the expression of cancer cells.”

AFP464 has been in Phase I clinical trial for the last year and a half, in which doses were given to patients with solid tumors. Dr. Burger said the next step is to take the anti-cancer agent to the second phase, where researchers administer to triple-negative breast cancer patients the drug alone or in combination with vorinostat. She expects that to occur in the next year and said that Karmanos could host one of those second-phase trials.

“We are currently conducting animal experiments with the single agents and the drug combination,” Dr. Burger said. “Triple-negative breast cancers might respond against that drug (AFP464).”

Triple-negative breast cancer afflicts mostly young women under the age of 40 and is more prevalent in the African-American community. About 182,460 women in the United States were diagnosed with invasive breast cancer in 2008 and about 40,480 will die from the disease, according to the American Cancer Society. Dr. Burger said that about 14 percent to 18 percent of breast cancer cases are triple-negative.

She expects that this research could translate to real-world applications in the next five years.

“These are targeted agents that are being tested,” Dr. Burger said. “Having a drug available to treat triple-negative breast cancer would be a major step in fighting this disease.”

Sylvie Naar-King, Ph.D., and Deborah Ellis, Ph.D., both associate professors in the Department of Pediatrics and the Pediatric Prevention Research Center, secured a $2,427,811 grant for her “Multisystemic Therapy to Reduce Health Disparities in Adolescents with Asthma” study. Dr. Naar-King will serve as principal investigator for the study and Dr. Ellis will serve as co-investigator.

Asthma, Dr. Naar-King said, is the most common cause of hospitalization for children after infections. Minority children living in urban areas, especially adolescents, appear at risk for higher rates of frequency of the condition and higher rates of death from asthma.

“Poor illness management is thought to be a primary driver of asthma morbidity and mortality,” Dr. Naar-King said. “Yet, there are very few randomized controlled trials with inner-city adolescents with asthma.”

The complexity of asthma management, she explained, requires intensive, “multi-component” interventions to improve the lives of the children at highest risk.

Study investigators will use Multisystem Therapy to improve asthma management, and reduce emergency department visits and hospitalizations due to asthma attacks among high-risk African-American children ages 12 to 16 who have moderate to severe asthma. Children who have been hospitalized at least once in the past year meet the high-risk qualification.

Multisystem Therapy consists of counselors going into the homes of asthmatic children to advise families on how best to change their environment and develop systems to ensure children adhere to schedules for medicine so that an attack does not spiral into a trip to the emergency room. The counselors also help families locate experts who can help adapt the home environment to make it more hospitable to asthmatics and make certain the teens have a primary care physician they see.

The study calls for a randomized controlled trial with 170 adolescents. Eighty-five will receive standard multidisciplinary specialty care and serve as a control group. The other 85 will receive standard care and MST. Families enrolled in the study will complete an initial data collection session, a seven-month post-test designed to coincide with treatment completion and a post-test at 12 months.

“If successful, this intervention will provide immediate assistance to a vulnerable population disproportionately affected by asthma and may reduce costs of care for this high risk population,” Dr. Naar-King said.

Enrollment in the study, which began in January, continues. Families interested in taking part in the study can call Karen Kolmodin at (313) 966-2366.

This study will use a variety of technologies to study why the corneas  -- the front, dome-shaped transparent tissue of the eye -- in many diabetic patients have delayed wound healing. In light of an ever-increasing patient population with diabetes and the lack of effective treatments for the disease, this study is of paramount importance.

Dr. Yu has received funding for this project since 1995. In 2008, he was awarded a five-year, $1.9 million grant to continue his research, bringing the total project period to 18 years.

In addition to the renewal of his ongoing project, Dr. Yu was also awarded a second R01 in 2008 from the NEI to identify ways to mediate the innate immunity of the eye, leading to the development of natural defense mechanisms against bacterial keratitis, a sight-threatening corneal disease associated with trauma and contact-lens wearing.