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UTHealth neuroscientist wins prominent NIH Director’s Pioneer Award

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UTHealth neuroscientist wins prominent NIH Director’s Pioneer Award

This balancing act of oxidative stress is particularly likely to go haywire in beta cells, the insulin-producing cells that malfunction and then start to die off in type 2 diabetes.

Scientists at Joslin Diabetes Center now have found that a relatively little-studied enzyme plays a central role in defending beta cells against oxidants, but is damaged by the high levels of blood glucose produced in diabetes.

Joslin Principal Investigator Robert Stanton, M.D., who led the research, says the discovery raises hopes of finding drugs that protect the enzyme, and thus the beta cells and their insulin production. Such drugs could help to stem the tide against type 2 diabetes, which now afflicts more than a quarter of a billion people worldwide.

Scientists in the Stanton lab previously had found that lowered activity of the enzyme G6PD, the main producer of an antioxidant called NAPDH, can inflict damage on several cell types.

In fact, Zhaoyun Zhang, a postdoctoral fellow and first author of the paper published in The FASEB Journal online on Dec. 23, was investigating G6PD activity’s effect on other cell types when she made the initial discovery about beta cells.

In her earlier project, whose results were published in The FASEB Journal in October, she was examining the diabetes-like complications that appeared in a line of mice modified to produce less G6PD.

Zhang hadn’t planned to look at the pancreas, which is where the insulin-producing beta cells are packaged together with other hormone-producing cells in structures called islets.

But she and Chong Wee Liew, a postdoctoral fellow in the neighboring lab of Principal Investigator Rohit Kulkarni, M.D., Ph.D., decided to take a look at islets in a pancreas from one of the experimental mice.

The islets were tiny compared to those in normal animals, suggesting extensive damage to the beta cells. “It was very, very surprising,” she recalls.

Zhang and her co-workers followed up with investigations of G6PD in beta cells and islets, as well as studies of mice with variations in G6PD activity (and thus in production of the NAPDH antioxidant).

“The research showed that NAPDH, an essential antioxidant upon which all cellular antioxidants ultimately depend, can regulate the growth and death of beta cells,” says Stanton, who also is Chief of the Nephrology Section at Joslin Clinic and Associate Professor of Medicine at Harvard Medical School.

The Joslin team went on to demonstrate that increases in the level of blood glucose cause a decrease in NAPDH that ends up killing beta cells-and that increasing the level of this antioxidant guards against this effect, at least in mouse beta cells.

“Preventing the death of beta cells or stimulating beta cells to grow is a kind of Holy Grail in diabetes prevention,” Stanton notes. “Treatments aimed at increasing this essential antioxidant hold great promise for treating or preventing diabetes in people.”

If this approach is successful, it could prove important for other illnesses as well. Abnormally high level of oxidants are thought to be a major cause of kidney disease, heart disease, hypertension, Alzheimer’s disease and many other conditions. “I hope that a new era of highly specific, targeted treatments will emerge that very effectively treat or possibly prevent many of these diseases,” Stanton says.

By adding another gas to the carbon dioxide used to inflate the surgical area during laparoscopy, researchers at Duke University Medical Center have found they can preserve more normal blood flow during noninvasive surgery.

The gas ethyl nitrite (ENO) helped to open blood vessels and keep blood flowing, which kept organs functioning normally during laparoscopy on pigs. The researchers did not complete any medical procedures on the pigs, which are similar in size and anatomy to humans. They merely created a laparoscopy situation by inflating the belly with carbon dioxide gas mixed with ENO. They then measured changes in heart rate, arterial pressure, cardiac output, organ blood flow, and certain chemical parameters like creatinine, a measure of kidney function, and cortisol, a stress-related hormone.

“We didn’t see any downside to using ethyl nitrite during this study of minimally invasive surgery,” said senior author James D. Reynolds, Ph.D., an associate professor of anesthesiology and member of the Duke Endosurgery Center. The study was published in the December issue of the journal CTS: Clinical and Translational Science.

“ENO has previously been administered to humans with no observed adverse effects, so it should be relatively easy to move this idea into a surgical clinical trial,” Reynolds said.

By preserving blood flow and organ status, the use of ENO could improve outcomes and reduce the time of in-hospital recovery, he said. “It is promising news for surgical patients.”

During the study, the research team determined that CO2 inflation produces “acute reductions in nitric oxide (NO) bioactivity,” Reynolds said. Nitric oxide is now being recognized as the third vital blood gas in the body, along with oxygen and carbon dioxide. A reduction in its bioactivity can lead to reduced organ blood flow and a rise in markers of acute tissue injury.

“Including an agent like ethyl nitrite restored the NO bioactivity, which is then conveyed by the red blood cells to increase blood flow,” Reynolds said. The team tested several different concentrations of ENO (1-300 parts per million) and found 10 ppm to be optimal.

Reynolds, who is also the chair of the Duke Institutional Animal Care and Use Committee, said that in the current study, adding ENO especially helped kidneys stay healthy. ENO kept serum creatinine and blood urea nitrogen concentrations constant, while in the group of animals inflated with carbon dioxide gas without ENO, both indicators increased, indicating a decline in kidney function.

Source - ErekAlert

The team—led by Mark Reed, Yale’s Harold Hodgkinson Professor of Engineering & Applied Science, and Tarek Fahmy, an associate professor of biomedical and chemical engineering—used nanowire sensors to detect and measure concentrations of two specific biomarkers: one for prostate cancer and the other for breast cancer.

“Nanosensors have been around for the past decade, but they only worked in controlled, laboratory settings,” Reed said. “This is the first time we’ve been able to use them with whole blood, which is a complicated solution containing proteins and ions and other things that affect detection.”

To overcome the challenge of whole blood detection, the researchers developed a novel device that acts as a filter, catching the biomarkers—in this case, antigens specific to prostate and breast cancer—on a chip while washing away the rest of the blood. Creating a buildup of the antigens on the chip allows for detection down to extremely small concentrations, on the order of picograms per milliliter, with 10 percent accuracy. This is the equivalent of being able to detect the concentration of a single grain of salt dissolved in a large swimming pool.

Until now, detection methods have only been able to determine whether or not a certain biomarker is present in the blood at sufficiently high concentrations for the detection equipment to give reliable estimates of its presence. “This new method is much more precise in reading out concentrations, and is much less dependent on the individual operator’s interpretation,” Fahmy said.

In addition to relying on somewhat subjective interpretations, current tests are also labor intensive. They involve taking a blood sample, sending it to a lab, using a centrifuge to separate the different components, isolating the plasma and putting it through an hours-long chemical analysis. The whole process takes several days. In comparison, the new device is able to read out biomarker concentrations in a just a few minutes.

“Doctors could have these small, portable devices in their offices and get nearly instant readings,” Fahmy said. “They could also carry them into the field and test patients on site.”

The new device could also be used to test for a wide range of biomarkers at the same time, from ovarian cancer to cardiovascular disease, Reed said. “The advantage of this technology is that it takes the same effort to make a million devices as it does to make just one. We’ve brought the power of modern microelectronics to cancer detection.”

LA JOLLA, CA—December 10, 2009—Researchers at The Scripps Research Institute have solved a 10-year-old mystery of how a single protein from an ancient family of enzymes can have two completely distinct roles in the body. In addition to providing guidance for understanding other molecules in the family, the research supplies a theoretical underpinning for the protein’s possible use for combating diseases including cancer and macular degeneration.

The research was published in the December 13, 2009 advance, online issue of the high-impact journal Nature Structural and Molecular Biology.

The scientists, led by Scripps Research Associate Professor Xiang-Lei Yang, focused on a molecule called human tryptophanyl-tRNA synthetase (TrpRS), finding that it contains a “functional switch” that enables it to perform two different functions. In one of its forms, the molecule acts to facilitate protein synthesis. In the second form, the same molecule works to inhibit the formation of new blood vessels—an effect that, if successfully harnessed, could be medically useful.

“I’m very excited about these findings,” said Yang. “This piece of work provides a very deep mechanistic understanding. It has really shown that the activity of this tRNA synthetase is of biological significance and that it’s a good example of the many, many different functions that have been found with the tRNA synthetase family.”

One Enzyme, Two Functions

For some time, scientists have known that the aminoacyl tRNA synthetase family is composed of 20 ancient enzymes that attach the correct amino acid to a tRNA as the first step in the synthesis of proteins.

The mystery of the protein family’s dual functionality, however, was born about a decade ago, with the publication of a 1999 paper in the journal Science by Paul Schimmel, who is Ernest and Jean Hahn Professor of Molecular Biology and Chemistry and a member of The Skaggs Institute for Chemical Biology at Scripps Research, in collaboration with a member of his lab at that time, Keisuke Wakasugi.

In the 1999 paper, Wakasugi and Schimmel showed that a member of the human aminoacyl-tRNA synthetase family, tyrosyl-tRNA synthetase (TyrRS), did more than adding the amino acid tyrosine to a protein chain during protein synthesis. In addition, a fragment of the protein could function to attract immune cells and to stimulate the growth of blood vessels.

The findings were met with astonishment and some skepticism in the scientific community.

Soon afterward, however, the Schimmel lab showed that another member of the family, TrpRS, also had a dual function. In addition to its role adding the amino acid tryptophan to a protein chain during protein synthesis, a fragment of TrpRS could inhibit new blood vessel formation.

Since that time, there has been considerable therapeutic interest in TyrRS, TrpRS, and other members of the aminoacyl-tRNA synthetase family. As a pro-angiogenic factor, the TyrRS fragment could be useful in diseases where growth of blood vessels is desirable, such as in some forms of heart disease or peripheral artery disease. Likewise, the TrpRS fragment’s anti-angiogenic effects could help patients reduce undesirable blood vessel growth in diseases such as cancer and a great many eye diseases that lead to catastrophic vision loss.

In fact, fragments of TrpRS were used as part of a study led by Scripps Research Professor Martin Friedlander that successfully halted the progression in animal models of highly vascular brain tumor and neovascular eye disease (PNAS 2007 104:967-972).

Despite the interest in tRNA synthetases, however, no one has been able to figure out exactly how they perform their different roles—until now.

Mystery Mechanism Revealed

In the current study, the research team used a combination of techniques including structural modeling analysis, mutagenesis, and cell-based functional studies to unravel the secrets of TrpRS.

The scientists identified the specific molecular changes that enabled TrpRS to perform one function or another.

In the study, the scientists show that, for its role in protein synthesis, TrpRS is typically in its full-length form. This form of the molecule contains a tryptophan-binding pocket that enables it to bind with the amino acid and shepherd it to where it is needed in protein synthesis.

In the second active form, however, the protein must first be broken into fragments by the body, creating a piece called T2-TrpRS. With the removal of the end of the full-length protein (the N-domain), new grooves in the T2-TrpRS protein fragment are revealed. Containing the now-exposed tryptophan-binding pocket, the grooves fit together with side chains of another molecule, VE-cadherin—known to be indispensable for proper vascular development.

Interestingly, the new study found that tryptophan acts to inhibit of the vasculature function of TrpRS, locking the protein into its protein-synthesis form.

Therapeutic Potential

Yang notes that the therapeutic potential of TrpRS and other tRNA synthetases are particularly good because they normally exist in abundant amounts in the body.

“Naturally, you’d imagine the body’s tolerance for such a protein is pretty good,” she said, “and we could use the activated form of the molecule.”

In addition, Yang points out that TrpRS is intriguing because it does not effect existing blood vessel growth, only new blood vessel formation, reducing the odds of negative side effects from its use.

Press Release By EurekAlert

Parkinson’s disease is an age-related disorder where the person loses certain types of brain cell, has slow speech and impaired and irregular movements.

Huang told the press that:

“The disease is currently diagnosed by tremors at rest and stiffness in the body and limbs.”

“But by the time we diagnose the disease, about 50 to 80 percent of the critical cells called dopamine neurons are already dead,” she added.

Disease experts already know that “the later stages of Parkinson’s disease (PD) are characterized by altered gait patterns”, wrote the authors.

Decreased arm swing while walking is the most frequently reported motor dysfunction in people with Parkinson’s, and yet altered gait patterns in the upper body are not as well documented as for the lower body in the early stages of the disease.

So Huang and colleagues decided to compare arm swing magnitude and asymmetry in patients with and without Parkinson’s and produce some measures that could help with early assessment of the disease.

“We know that Parkinson’s patients lose their arm swing even very early in the disease but nobody had looked using a scientifically measured approach to see if the loss was asymmetrical or when this asymmetry first showed up,” explained Huang.

Huang and colleagues tested their assumption, that because Parkinson’s is an asymmetrical disease, the arm swing on one arm will be lost first compared to the other.

For the study, using an optically-based motion capture system, the researchers measured the arm swing of 12 people who had three years earlier been diagnosed with Parkinson’s, and also of eight people in a control group.

The motion capture system entailed the participants wearing many reflective markers and then being tracked by eight digital cameras that captured the exact position of each main part of the body while walking.

Special software analyzed data from the camera images:

“When a person walks, the computer was able to calculate the degree of swing of each arm with millimeter accuracy,” explained Huang.

The Parkinson’s patients were in “off” state when the measurements were done: that is they stayed off their medication overnight to stop it affecting the test results.

The participants were asked to walk at a normal and a fast pace, and then on their heels (to minimize push off).

“Arm swing was measured as the excursion of the wrist with respect to the pelvis,” wrote the authors, who compared arm swing magnitude for each arm, as well as inter-arm symmetry between the Parkinson’s group and the control group.

The results showed that:

• Both groups had comparable gait velocities.
• There was no significant difference between the Parkinson’s group and the control group in the size of arm swing in all walking conditions for the arm that swung more or less.
• However, what was striking was that compared to the control group, the Parkinson’s group showed significantly greater asymmetry in their arm swing (one arm swung significantly less than the other while walking).
• The Parkinson’s group asymmetry angle was 13.9 ± 7.9 per cent compared to 5.1 ± 4.0 per cent for the control group (p = 0.003).
• When the participants walked faster, the arm swing increased but the amount of asymmetry stayed the same.

Huang and colleagues concluded that:

“Unlike arm swing magnitude, arm swing asymmetry unequivocally differs between people with early PD and controls.”

“Such quantitative evaluation of arm swing, especially its asymmetry, may have utility for early and differential diagnosis, and for tracking disease progression in patients with later PD,” they suggested.

Huang said they believed this was the first time that arm swing has been shown to be a potentially early sign of Parkinson’s disease.

While people without Parkinson’s show some irregular arm swing when they walk, the asymmetry is much larger in those who have the disease, said the researchers.

Huang said this could be a useful way to help early detection of Parkinson’s:

“There are wide scale efforts to find drugs that slow cell death. When they are found, they could be used in conjunction with this technique to arrest or perhaps cure the disease because they could be given before great damage has occurred,” she explained.

The study was funded by the National Institutes of Health and the University of North Carolina Center for Human Movement Sciences.