University Times

Neurology research grants announced

The Department of Neurology recently announced the following grants:

• Edward A. Burton, professor of neurology, molecular genetics and biochemistry, has been awarded a grant from the Dystonia Medical Research Foundation for his project, “Dopamine neuron development in a novel zebrafish model of DYT1 dystonia.”

• Guodong Cao was awarded a National Institutes of Health grant for his project, “Novel modified erythropoietins for the treatment of ischemic brain injury.”

• J. Timothy Greenamyre, chief of neurology’s Movement Disorders Division, received an award from the Michael J. Fox Foundation for “Characterization of E46K and A53T alpha-synuclein BAC transgenic rats” and from the Parkinson’s Disease Foundation for “Modeling gastrointestinal dysfunction in PD.”

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Glowing ozone detector developed

Pitt researchers have developed a fluorescent substance that glows bright green when exposed to ozone in the air or in biological samples such as human lung cells.

The Pitt team reported in Nature Chemistry that their simple and fast-acting detector can function as a consumer device to measure surrounding ozone, or as a laboratory tool that could provide insight into ozone’s effect on the human body and its debated role in the human immune system.

The team’s small molecule-based probe, when added to regular distilled water, causes ozone to react, ultimately producing a substance that glows bright green under an ultraviolet lamp or microscope.

They say the probe differs from existing ozone-detection methods in that it is sensitive only to ozone. Current indicators can register a false positive in response to humidity, other reactive oxygen species and atmospheric compounds such as lead, palladium and platinum.

Chemistry professor Kazunori Koide, the paper’s corresponding author, said, “As you inhale air, you inhale ozone, and it is not known how deeply it penetrates the lung or its effect on the body. Patients with respiratory diseases who are more sensitive to ozone may be able to monitor their exposure, as should employees in industrial and laboratory jobs that include regular ozone exposure. Our method is quick, so people will know they’ve exceeded safe levels before they suffer the symptoms, and it’s highly specific to ozone, so it will prevent having false data.”

As an indoor and outdoor pollutant, ozone can irritate the lungs, particularly in people with asthma, bronchitis or cystic fibrosis. It is generated by certain electronic devices and also created from the reaction of high concentrations of pollution, such as car exhaust and UV radiation from the sun.

For the indoor experiment, paper strips coated with the fluorescent substance were left for eight hours in an unventilated office with two photocopiers and two laser printers, devices that are known to generate ozone. When exposed to UV light, the strips revealed concentrations of ozone captured from within the room.

To test the probe outdoors, the scientists placed the solution at four high-traffic areas in Pittsburgh for eight hours on a sunny day (but out of direct sunlight) and successfully detected ozone.

The probe also was tested on human lung fluid and blood serum, which glowed under a laser light after exposure to ozone. The researchers also exposed human lung cells treated with the probe to ozone-rich air for five minutes.

With a microscope, they observed the fluorescent glow expand within the cell, illustrating that ozone indeed penetrated the cell membrane. The probe’s successful use in biological samples could help unravel certain medical questions regarding ozone, including disputes over whether white blood cells emit ozone to fight inflammation and bacterial infections and ozone’s ability to penetrate the body. The researchers demonstrated that their probe can track ozone as it moves throughout a cell sample and possibly help scientists gain insight into the molecule’s activity within cells.

Koide worked with professors George Leikauf, Claudette St. Croix and department chair Bruce Pitt of the Department of Environmental and Occupational Health, and lead author graduate student Amanda Garner and postdoctoral student Shin Ando, both of the Department of Chemistry.

The paper can be found at www.nature.com/nchem.

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Anti-aging research published

The secret to longevity may lie in an enzyme that has the ability to promote a robust immune system into old age by maintaining the function of the thymus, according to a study of genetically modified mice that live 30 percent longer than a typical mouse.

The study, led by Abbe de Vallejo, professor of pediatrics and immunology in the School of Medicine and immunologist at Children’s Hospital, reports that the novel mouse model has a thymus that remains intact throughout its life. In all mammals, the thymus — the organ that produces T cells to fight disease and infection — degenerates with age.

“These findings give us hope that we may one day have the ability to restore the function of the thymus in old age or, perhaps by intervening at an early age, we may be able to delay or even prevent the degeneration of the thymus in order to maintain our immune defenses throughout life,” said de Vallejo.

Researchers deleted an enzyme in the mice known as pregnancy-associated plasma protein A (PAPPA). In addition to living longer, PAPPA-knockout mice have a significantly lower occurrence of spontaneous tumors than typical mice.

PAPPA controls the availability in tissues of a hormone known as insulin-like growth factor (IGF) that is a promoter of cell division. IGF is required for normal embryonic and postnatal growth but also is associated with tumor growth, inflammation and cardiovascular disease in adults.

By deleting PAPPA, the researchers were able to control the availability of IGF in tissues and dampen its many ill effects. In the thymus, deletion of PAPPA maintained enough IGF to sustain production of T cells without consuming precursor cells, thereby preventing the degeneration of the thymus.

“Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune protection throughout life,” de Vallejo said. “This study has profound implications for the future study of healthy aging and longevity.”

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Donated tissue fosters IPF study

The first findings from a unique patient-driven effort to provide lung tissue for research might help doctors predict when patients with idiopathic pulmonary fibrosis (IPF) are becoming dangerously ill and also could point the way to interventions that could sustain them until life-saving transplants can be performed.

According to senior author Naftali Kaminski, professor of medicine, computational biology and pathology and director of the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases at the School of Medicine and UPMC, the research published in the American Journal of Respiratory and Critical Care Medicine addresses why some IPF patients experience rapid declines that damage the lung alveoli, the tiny sacs where the exchange of oxygen and carbon dioxide occurs.

“Approximately 10 percent of patients develop an acute phase that in most cases is lethal,” Kaminski said. “There has been very little understanding of the molecular basis of this syndrome, but because of the dedication of our patients and their families, we are getting closer to some answers.”

In comparing the gene activity profile of the lungs of eight IPF patients whose disease was worsening dramatically when they died with those of 23 stable IPF patients and 15 people with healthy lungs, researchers found the gene activity patterns to be more similar among all IPF patients compared to healthy people, said lead author Kazuhisa Konishi, a visiting postdoctoral fellow in Kaminski’s lab who performed the gene profiling. “But nearly 600 genes were differentially expressed between IPF patients who had accelerated disease and those who were stable.”

He saw no evidence that infection or inflammation caused the disease acceleration, but found indications that the cells of the alveolar epithelium — the tissue that covers the surface of the air sacs — were dying rapidly.

Study co-author Kevin Gibson, professor in the Division of Pulmonary, Allergy and Critical Care Medicine and medical director of the Simmons Center, said that could mean that drugs used to protect the epithelium in other illnesses, such as cancer, might help IPF patients survive an exacerbation, giving them a chance for a lung transplant.

With the help of Kaminski’s longtime collaborator Dong Soon Kim of Asan Medical Center and the University of Ulsan in Seoul, South Korea, the Pitt researchers found that levels of a protein called alpha-defensin were particularly high in the blood of patients experiencing an exacerbation. If the findings are verified with more research, which is underway, the proteins could be the first biomarker blood tests that could identify patients at risk for sudden deterioration of lung function.

If not for the altruism of IPF patients, the research would not have been possible, Kaminski noted. The IPF tissue samples used for the study were collected through the Simmons Center’s warm autopsy program, billed as the only one for lungs in the world. Simmons Center nurse and study co-author Kathleen Lindell developed the program several years ago, after an IPF patient indicated he wanted to aid research efforts by donating his lungs to science after death.

“The tissue has to be collected within six hours of death, so it demands a great deal of flexibility and commitment on the part of caregivers and family,” Lindell said. “The gene components of the lung cells degrade very quickly, so without the warm autopsy protocol, we couldn’t have done the activity profiling that was the foundation of this research.”

Other Pitt co-authors are Thomas J. Richards and Yingze Zhang of the Simmons Center; Rajiv Dhir, Michelle Bisceglia and Samuel A. Yousem, Department of Pathology, and Sebastien Gilbert, Department of Thoracic Surgery.

The research was funded by the National Institutes of Health and the Dorothy P. and Richard P. Simmons Endowed Chair for Interstitial Lung Diseases.

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The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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