Discovery Engine

Longest-running NIH grant focal point of UMMC Research

An $11.5 million grant from the National Institutes of Health will keep the University of Mississippi Medical Center’s flagship research program –  a 41-year investigation into the cardiovascular system – running.

Dr. Arthur C. Guyton began the program project grant, Cardiovascular Dynamics and their Controls, in 1968. Since then, the program has branched into studies of specific illnesses.

When the latest grant expires in November 2013, the program will be one of the longest-running program project grants in NIH history.

So, what have taxpayers gotten in return?

Dr. John Hall, associate vice chancellor for research and the program’s principal investigator, said it’s provided well-paying jobs, tax income for the state, deeper scientific knowledge and lifesaving medical advances.

“It’s given us a focal point for our research at the Medical Center. This is not the only grant in our department, but it’s the engine,” he said. “The vast majority of the grants in the department are offshoots of this program.”

The latest grant, received in December, will fund support services for scientists throughout the Medical Center and four studies under the program umbrella. Those studies, each with a project leader, are highlighted in this Centerpiece.

High blood pressure post-menopause

Before menopause, women’s blood pressure usually remains lower than men’s. But after menopause, things can swap. And there’s no clear reason why.

That gender-based crisscross intrigues Dr. Jane Reckelhoff, professor of physiology and biophysics.

Her study examines the effect salty diets have on rats: male, female, castrated males and ovariectomized females.

By analyzing kidney function, she hopes to find why androgen sex hormones in males tend to accelerate the renal-cortical-endothelin system and oxidative stress while estradiol in females tends to protect against increases.

In her grant proposal, Reckelhoff wrote that testing would use an integrative approach of physiological, biochemical and molecular methods.

Not only does the project grant support her study, but it’s funded three core facilities in the Department of Research used by scientists like her.

Those facilities are administrative (which Hall oversees), analysis and computer-technology, run by Dr. Robert Hester. The cores provide a shared backbone of resources, which provides quality control and saves money.

Effect of sympathetic nervous system on hypertension

The carotid sinus node, part of the sympathetic nervous system, acts like a thermostat: When blood pressure rises too much, the node kicks electric impulses to the brain, calming things down.

Dr. Tom Lohmeier, professor of physiology and biophysics, wondered if, by continually stimulating the nerve, the brain would lower blood pressure long-term.

Working with a Minneapolis Minn.-based company – CVRx – they developed a sort of pacemaker implant for the node. A 150-patient test now in its final stage lowered blood pressure an average of 20 mm of mercury.

“That’s a significant, long-term effect,” Lohmeier said. “We are tricking the brain into thinking blood pressure is too high.”

Lohmeier still wants to know more about the interplay between the sympathetic nervous system and the kidneys.

Diminished sympathetic-nervous-system activity lets the kidneys secrete more water and salt, he said. “This goes back to what Dr. Guyton stated 30 years ago, that the kidney is a long-term regulator of blood pressure.”

Through the six-year study, he’s relied heavily on resources built by the cardiovascular dynamics grant, from computer data support to the assay lab.

“There’s so much available here,” he said. “Because of the (program) and our core facilities, we can really get into the mechanisms that allow this sympathetic nervous system suppression to occur.”

The function of preeclampsia

Dr. Joey Granger, dean of the School of Graduate Studies in the Health Sciences, focuses on preeclampsia, a condition in 5 to 10 percent of U.S. pregnancies.

In preeclampsia, blood vessels in the uterine wall don’t enlarge as they should and instead restrict blood and oxygen to the placenta and fetus.

In expecting moms, risk factors include hypertension, obesity, diabetes, age, multiple births and multiple-fetus pregnancies.

“There is no treatment for it except for bed rest and early delivery,” Granger said.

Granger and his team are searching for drugs that can increase blood flow into the placenta. One team member from the early part of the decade is Barbara Alexander, associate professor of physiology and biophysics.

“I got my start in Dr. Granger’s lab, working as a fellow on the preeclampsia research,” she said.

Besides her own hypertension-related studies, Alexander oversees the analysis core facility. It provides scientists with imaging and microscopes, molecular assays, biochemical analysis, statistics support and more.

“Mississippians, I believe, on a population basis, have more cardiovascular-related deaths than any other state,” she said.

“So that . . .speaks to why this work is so important.”

Obesity-related hypertension

Hall’s portion of the project uses genetics to probe the connections between obesity and high blood pressure.

Fat secretes a hormone called leptin that acts on the brain to suppress appetite and stimulate energy expenditure in the muscles. As people become obese, leptin stops acting like it should.

“Your blood pressure goes up, but not your oxygen and glucose use, and it doesn’t suppress your appetite,” Hall said.

By knocking out certain genes, he can block independently the signaling systems for blood pressure, oxygen-and-glucose consumption and appetite.

Isolating the signaling system for blood pressure led researchers through the sympathetic nervous system to the kidneys. Through those pathways, increased amounts of leptin tend to push the kidneys into overdrive, creating hypertension.

“We’re trying to understand the basic physiologic aspects that go wrong causing high blood pressure,” Hall said.

The entire program has created a synergy in the Department of Research. Professionals working on the program include engineers, biologists, biochemists, computer techs and more.

“The whole is more than the sum of the parts. The investigations do more together than they could have done individually,” he said.

The Cardiovascular Dynamics and their Controls program

•  currently supports 44 people directly and has aided nearly every researcher at the Medical Center,

•  brought $23 million in federal money into the state during the last 10 years and more than $30 million during the last 15,

•  helped the Medical Center build a strong cardiovascular program,

•  launched the careers of young scientists,

•  produced 402 publications in the last five years and thousands during its lifespan,

•  provided foundational knowledge for modern treatment of heart failure and hypertension,

•  played a role in understanding the renal angiotensin system that led to the development of the best and most widely used drugs to treat hypertension, and

•  played a role in understanding pulmonary edema and the development of drugs to treat it.

-Jack Mazurak

2009-05-11 00:00:00 18914