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Home > ARRA Stories > Profile in Translation: LINCCing University of Iowa Laboratory & Clinical Scientists To Study Causes of Aortic Aneurysms
Profile in Translation: LINCCing University of Iowa Laboratory & Clinical Scientists To Study Causes of Aortic Aneurysms

By Jenn Laskowski

March 10, 2010

Photo of Peter Rubenstein and Heather Bartlett

Dr. Peter Rubenstein, University of Iowa (UI) professor of biochemistry, has spent many years in the lab investigating actin, a major protein involved in various muscular and cellular processes including contraction, movement, and shape development. He's recently partnered with Dr. Heather Bartlett, a pediatric cardiologist, to better understand how mutations in actin lead to aneurysms of the aorta in certain individuals. This collaboration is the result of many dynamic conversations and a $50,000 award from an America Recovery and Reinvestment Act-supported ICTS administrative supplement called Looking into Clinical Connections (LINCC), a faculty development program that links pairs of laboratory and clinical scientists by funding them with pilot awards.

Dr. Rubenstein is widely considered to be a leading expert in actin research. He had just finished presenting to his colleagues about mutations in actin that lead to the onset of deafness when he was approached by Dr. Heather Bartlett, who is also an assistant professor of pediatrics at the UI.

"I didn't know you were working on this! Maybe you can help me," she said. Dr. Bartlett proceeded to tell Dr. Rubenstein about one of her patients, an individual with actin mutations and a long family history of aortic aneurysms. She specifically wanted to know how she should treat her patient and if there was anything she should be especially concerned about.

"Well," he said, "the answer is 'We don't know.'" Aside from surgery, no current treatment exists to correct the inborn error in this important structural protein. Furthermore, based on the mutation, intervening surgically could change things and cause something else to happen.

"But we have no idea about this mutation," said Dr. Bartlett. "We don't know how to prevent dilation or when the size of the aorta is dangerous enough to warrant intervention," she added. Without the funds in place to actively pursue an investigation, the duo had to settle for throwing around hypothetical questions and bouncing ideas off one another in an on-going series of hallway conversations.

Then they heard about the new ICTS Looking into Clinical Connections (LINNC) faculty development program which has been piloted in the Carver College of Medicine. LINCC is an American Recovery and Reinvestment Act-supported CTSA administrative supplement that was awarded to the Institute for Clinical and Translational Science. It provides pilot grants and is available from 2009 – 2011. Dr. Rubenstein is one of five basic scientists at the UI that has received a $50,000 LINCC award for his collaborative work. The LINCC program is designed to help ease the process of moving lab discoveries into the clinic and provides pilot grants to facilitate new collaborations that partner basic science with clinical medicine at the UI. The grant may provide protected time, facilities, personnel support, or equipment to successfully partner clinically active faculty with basic science faculty to energize their research activities. The program intends to support 10 pairs of clinical and basic scientists during its pilot stage. Advertising for the second round of LINCC awards will begin at the end of spring semester with a summer due date.

"We wrote this LINCC project together," said Dr. Rubenstein, "with the idea that we have a beautiful system in place for studying actin and deafness, so why don't we just do the same thing with actin and aneurysms?" The LINCC collaboration appears to be a natural marriage for these two. Dr. Bartlett brings the biological expertise to the table, while Dr. Rubenstein's entire lab is set up to get things done from a biochemical standpoint.

The lab has particular expertise in understanding how actin works as a molecule, where proteins bind to it, how it is regulated, and what to look for, so now they can combine this basic scientific knowledge with patient symptoms to reveal more about the disease's etiology. Ultimately, they hope to develop a grant in which Dr. Bartlett will serve as the principal investigator, "And we'll help out," Dr. Rubenstein said with a big smile.

"You know these mutations cause disease, but that's black box. You don't know the molecular basis by which that disease process occurs," he said. Observing the structural defects in the filaments, caused by the actins in their initial experiments, allows Drs. Bartlett and Rubenstein to gain molecular insight into the effects of the mutations, and understand why these patients end up with aneurysms.

Drs. Rubenstein and Bartlett have already expressed aneurysm-causing mutations in yeast actin and have studied two of the nine mutations. As a result, they have found defects that give insight into why muscle wall weakness may occur and may lead to the aneurysms.

The vessel wall contains a muscle layer that opens and closes the tubular interior. In doing so, it controls complex processes like blood pressure. A dissecting aneurysm can occur when the muscle layer is torn and normal pressure causes the area to balloon out. If the balloon breaks, a patient can bleed to death. Drs. Bartlett and Rubenstein think that this disease somehow has to reflect alterations in actin function brought about by these abnormalities.

Since actin needs to transduce force and withstand pressure then the filament must be strong and intact, as opposed to weak and stringy. "So far, we're finding that these filaments are much less stable than they normally would be which could cause the ballooning effect," Dr. Rubenstein explained.

Their approach includes bringing an understanding of pathology down to a molecular level, "And then back again," Dr. Bartlett said. This circular process allows the investigators to gain a tremendous amount of insight into understanding the development and regulation of vascular function in a normal human.

Ultimately, this information could provide potential insight into how you treat the disease with pharmaceuticals as opposed to, "Cutting it out and patching it, which is what they are doing now," said Dr. Rubenstein, adding, "It's functional, but it's better to treat it with a pill."

"We've still got about seven more mutations to go, and everything is coming along just fine," Dr. Rubenstein said. Although other actin labs in the country have studied skeletal muscle myopathy causing mutations, nobody else has, as of yet, systematically examined smooth muscle actin mutations that cause disease, which puts Dr. Rubenstein's lab in a unique position to work on this new research.

LINCC funds also enabled Dr. Bartlett to accompany Dr. Rubenstein to a basic science meeting which he attends each year. Much of the meeting is devoted to actin, so Dr. Bartlett was able to learn about the protein while meeting various experts in the field.

"It's been great fun for both of us. I'm learning new things and it's fun to think about problems from a new perspective," said Dr. Bartlett.

"And I have one more person to boss around," Dr. Rubenstein teased.

Meanwhile, there's no end in sight to their hallway conversations which have transformed into a hypothetical basketball game of sorts:

"I think there is a lot of potential for a lot of long range projects that will come out of this and it would be really neat if we could figure out a way to extend this up into the physiological realm," Dr. Rubenstein set up the play.

Dr. Bartlett defended, "We could do that, though."

"We'd have to get a mouse," he said, moving quickly down the court.

Slamming the hypothetical ball into the hole, Dr. Bartlett quipped, "I could call around."

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