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UT researcher cures high blood pressure in rats

A University of Toledo researcher recently won a prestigious award for his cutting-edge hypertension study that cured high blood pressure in rats.

Dr. Xi Cheng, a UT College of Medicine postdoctoral fellow, won the Physiological Genomics Group New Investigator Award from the American Physiological Society and presented his research in April at the Experimental Biology meeting in San Diego.

Cheng

In his trailblazing research, Cheng identified a gene responsible for inherited high blood pressure in rats, and then he genetically engineered that gene to cure hypertension in the rats. Both were firsts in the field of genomic science that is focused on essential hypertension.

About one in three U.S. adults suffers from essential hypertension, or high blood pressure, which is a complex condition with no clear cause. Blood pressure can be affected by environmental factors such as diet and weight, but hypertension also runs in families with no identifiable, pre-existing cause. This kind of hypertension is what interests the UT researchers.

Cheng also discovered that another kind of genetic material — circular RNA — also seems to play a role in hypertension. His paper, published last fall in Physiological Genomics, was chosen as an APSselect article, an award given to authors of the most exciting original research articles published by the American Physiological Society.

Cheng has been studying hypertension since 2013, when he came to UT as a doctoral student in molecular medicine. He continues to work with his mentor, Dr. Bina Joe, Distinguished University Professor and chair of the Department of Physiology and Pharmacology, and director of the Center for Hypertension and Personalized Medicine. Their research focuses on how to correct and, if possible, permanently cure hypertension.

Scientists believe patients with hypertension inherit multiple genetic defects, which are difficult for researchers to find on strands of DNA that are millions of base pairs long. It’s also difficult to prove whether the defects “cause” or are “associated” with high blood pressure.

Cheng identified a new gene that regulates blood pressure in rats and pinpointed the mutation that is inherited and causes high blood pressure. He found a 19-base sequence of DNA in rats with lower blood pressure that was missing in rats with higher blood pressure.

Using a new technology, he extracted that critical DNA sequence from the rats with normal blood pressure and inserted it into the genome of hypertensive rats to see if correcting the mutation would cause their blood pressure to decrease. It was the first time anyone had used the new technique, called CRISPR/​Cas9 technology, to perform genome surgery in rats for correcting mutations for hypertension.

The embryos with the edited gene were implanted into surrogate mother rats. When the rodents were born, they became the world’s first genetically altered rats created to pinpoint the area on their DNA that caused them to inherit hypertension. More importantly, Cheng’s new rat strain no longer had high blood pressure. The “cure” had worked.

Cheng’s first-of-its-kind research proved that genome surgery — editing genes — can permanently cure a genetically inherited cause of hypertension in rats.

Allen Cowley, an internationally renowned hypertension researcher at the Medical College of Wisconsin, remarked in his review of Cheng’s work that “the work represents a technical tour de force and illustrates the critically important role of animal models that can mimic human traits of a complex disease to advance our understanding of the polymorphic associations that have been defined in human populations.”

Human patients can’t throw out their blood pressure meds just yet, though.

“Additional research will determine the possibility of this approach to cure hypertension in humans as we work to identify all the genetic pieces within the human genome that contribute to hypertension,” Cheng said.

The particular region that controls blood pressure in rats is similar to a region on a chromosome in humans in which scientists have reported associations with cardiac dysfunction and high blood pressure.

It’s much more difficult, though, to test this in humans, whose genes vary in millions of ways from person to person. To pinpoint the piece of genetic material that causes high blood pressure is like finding that proverbial needle in a haystack.

But the researchers are hopeful about the future of the research being conducted at the Center for Hypertension and Personalized Medicine.

“Here in Toledo, we are contributing to a piece of the puzzle,” Joe said. “When Xi and I were born, we didn’t have genome sequencing ability. Now we do.”

In the future, she said, scientists will use artificial intelligence and machine learning to predict who will get what diseases. And those scientists will rely on researchers like Joe and Cheng for data and to understand the blueprint of the genome.

Cheng has been accepted into a highly competitive online master’s program in computer science and machine learning at the Georgia Institute of Technology and will apply what he learns in the program to his research in Toledo.