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Release: Sept. 26, 2000

UI researchers use new strategies to explore the secrets of the genome

IOWA CITY, Iowa -- Last June scientists from the Human Genome Project and Celera Genomics announced that they had completed the working draft of the human genome. The news that the 3.1 billion bases -- the chemical units that make up DNA -- of the human genome had been sequenced was greeted with much fanfare. President Clinton called it "the most wondrous map ever produced by humankind." But what does it really mean? Perhaps the most important question we should be asking is "what next?"

University of Iowa researcher Robin Davisson, Ph.D., assistant professor of anatomy and cell biology, is one scientist who is already working on that question.

"Knowledge of the genome sequence is the beginning, but the key is to understand how genes function in the whole organism," Davisson said.

Davisson’s research group is using a new, emerging technology called functional genomics. By manipulating the genome in very selective ways, researchers can study how those manipulations affect the physiology of the whole organism.

"By looking at the whole system, you get more information about what that gene is doing within the organism and how things are happening in concert," Davisson said.

The importance of this new branch of research was underlined by Mary J. C. Hendrix, Ph.D., Kate Daum Professor of Anatomy and Cell Biology and head of the department.

"This represents a brand new field in biomedical research. It has tremendous potential in terms of yielding new information on the structure and function of genes," Hendrix said.

Davisson’s research focuses on the cardiovascular system, primarily blood pressure regulation. Her research team is trying to understand the genetic causes of high blood pressure and the molecular basis of consequences of this condition, such as heart failure.

Working with other UI researchers, Davisson recently published a study in the July issue of the Journal of Clinical Investigation, which she describes as a perfect example of functional genomics.

Angiotensin II is a small molecule found almost everywhere in the body. It helps to control blood pressure and thirst by interacting with its receptor. In rodents’ brains the angiotensin receptor has two subtypes, which are almost identical. In fact, until now it was impossible to tell if they had separate roles in the cardiovascular system. Davisson’s research team bred genetically altered mice, which had one receptor subtype or the other but not both. When the mice received angiotensin in their brains, mice with one receptor subtype showed an increase in blood pressure but no effect on thirst, measured by the drinking response. Conversely, mice with the other receptor subtype showed no change in blood pressure in response to the angiotensin, but the drinking response was significantly affected.

"We were able to take genetically altered mice and measure the physiological response to angiotensin in an awake, freely moving mouse," Davisson said. "Using this combination of genetic manipulation and physiology, we were able to get answers that were simply not available through any other route. One very important aspect of this study is that it validates this strategy of functional genomics."

While this study has shown different roles for each of the receptor subtypes, Davisson thinks that a new genetic manipulation strategy will allow even better understanding of the genetic control of blood pressure and fluid balance. Together with co-investigator, Martin D. Cassell, Ph.D., associate professor of anatomy and cell biology, Davisson plans to use a recently secured five-year, $1.3 million National Institutes of Health grant to continue her functional genomics work.

"Using this new genetic manipulation strategy, called the Cre lox P system, we can knock out genes in specific cell or tissue types or knock out genes at a particular time in the organism’s development."

The ability to "knock out," or delete, genes of the angiotensin system only in the brain provides a way to look at the brain system separately from the same system in the rest of the organism. The Cre lox P system also allows researchers to silence genes at specific times in the organism’s development.

"We can make the physiological measurements in the animal, silence the gene and then come back to that same animal and measure the physiological effect of losing the gene," Davisson said. "The genome sequencing efforts will result in a huge number of newly discovered genes. Now researchers have strategies to investigate the functions of those genes in whole organisms," Davisson added.

Other UI researchers using similar strategies to study important physiological phenomena include Curt D. Sigmund, Ph.D., UI associate professor of internal medicine, and physiology and

biophysics, and Kevin P. Campbell, Ph.D., a Howard Hughes Medical Institute investigator and UI Foundation Distinguished Professor of Physiology and Biophysics.

Hendrix agrees with Davisson about the potential of functional genomics.

"The data generated from animal models will have tremendous translational impact on human diseases," Hendrix said. "It will allow us to understand how specific genes are implicated in certain diseases and how we might be able to target them for future therapeutic approaches."

As head of the UI department of anatomy and cell biology, Hendrix intends that the UI begin offering training to graduate students, postdoctoral researchers and even junior faculty in this new technology. The new training should make scientists at the UI more competitive when they apply for grants and when they write publications.

"We want everyone to be capable and comfortable working with the new genes being discovered. Specifically, we want to train our researchers to be able to address questions about gene function and structure," Hendrix said. "We hope to train the new leaders in the field."

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