Melatonin delays ALS symptoms, deaths

Melatonin injections delayed symptom onset and reduced mortality in a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a study by School of Medicine researchers. The research team revealed that receptors for melatonin are found in the nerve cells, a result that could launch novel therapeutic approaches.

Annually about 5,000 people are diagnosed with ALS, which is characterized by progressive muscle weakness and eventual death due to the failure of respiratory muscles. But the causes of the condition are not well understood.

Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. After screening more than 1,000 FDA-approved drugs several years ago, the research team determined that melatonin is a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.

Said senior investigator Robert Friedlander, faculty member in the Department of Neurological Surgery: “Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS. We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases.”

Hoping to stop neuron death in ALS just as they did in Huntington’s, the research team treated mice bred to have an ALS-like disease with injections of melatonin or with a placebo. Compared to untreated animals, the melatonin group developed symptoms later, survived longer and had less degeneration of motor neurons in the spinal cord.

The report was published online ahead of its print publication in Neurobiology of Disease.

Co-authors included other scientists from the School of Medicine and the VA Pittsburgh Health Care System; Harvard; Ohio State; Weifang Medical University; Bedford VA Medical System; St. Joseph’s Hospital and Medical Center, and the University of Texas Medical School.

The project was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health (NIH); the U.S. Department of Defense, and the Muscular Dystrophy Association.

Mild blast brain injuries resemble Alzheimer’s

A multicenter study led by scientists at the School of Medicine shows that mild traumatic brain injury (TBI) after blast exposure produces inflammation, oxidative stress and gene activation patterns akin to disorders of memory processing such as Alzheimer’s disease.

Blast-induced TBI has become an important issue in combat casualty care. In many cases of mild TBI, MRI scans and other conventional imaging technology do not show overt damage to the brain.

Senior investigator Patrick Kochanek, a critical care medicine faculty member and director of the Safar Center for Resuscitation Research, said: “Our research reveals that despite the lack of a lot of obvious neuronal death, there is a lot of molecular madness going on in the brain after a blast exposure. Even subtle injuries resulted in significant alterations of brain chemistry.”

The research team developed a rat model to examine whether mild blast exposure in a device called a shock tube caused any changes in the brain even if there were no indication of direct cell death, such as bleeding. Brain tissues of rats exposed to blast and to a sham procedure were tested two and 24 hours after the injury.

Gene activity patterns, which shifted over time, resembled patterns seen in neurodegenerative diseases, particularly Alzheimer’s, Kochanek noted. Markers of inflammation and oxidative stress, which reflect disruptions of cell signaling, were elevated, but there was no indication of energy failure that would be seen with poor tissue oxygenation.

“It appears that although the neurons don’t die after a mild injury, they do sustain damage,” he said. “It remains to be seen what multiple exposures, meaning repeat concussions, do to the brain over the long term.”

Co-authors of the study included researchers from the Safar center and the School of Medicine; University of California-San Diego; ORA Inc.; Walter Reed Army Institute of Research; Dyn-FX Consulting; Uniformed Services University of the Health Sciences, and Integrated Services Group.

The project was funded by the Defense Advanced Research Projects Agency and reported in the online version of the Journal of Neurotrauma.

Adipose stem-cell-based vascular grafts developed

Researchers led by David A. Vorp, William Kepler Whiteford Professor of Bioengineering and associate dean for research at the Swanson School of Engineering, are moving toward the production of an adipose stem-cell-based vascular graft for bypass patients.

Over the next two years, the research group will begin the clinical translation of novel, autologous, stem-cell-based tissue-engineered vascular grafts. TEVGs present a novel recourse because the grafts are grown from the patient’s own cells, allowing for improved response from the body’s immune system and less reliance on using existing arteries and veins from elsewhere in the patient or from a donor.

Vorp’s team is using adipose or fat tissue because, he said, “fat not only contains an abundance of stem cells, but also is plentiful in most patients and a source that is generally attractive to the patient for harvesting.” With nearly a million aortocoronary bypass, peripheral arterial bypass and arterio-venous access graft procedures performed each year in the United States, there is a greater need for a more successful vascular graft that further reduces morbidity and mortality.

According to Vorp, “This work will focus on several important issues or open questions that must be addressed when considering the translation of this technology to the clinic. First, we must determine the minimum number of stem cells that must be harvested from the patient in order to build a successful TEVG. This is important since the cells are not unlimited in number and we have to be sure that there are enough obtained from a common liposuction procedure. Second, the age and sex of the patient may influence the ability of their cells to create a successful TEVG, and we must determine if this approach is appropriate for all patients, or if certain factors — such as male or female sex, or patients beyond a certain age — preclude this therapy.”

While the grafts will be constructed using stem cells from human donors, they will be tested in an established rat model to determine their efficacy for replacing a small artery.

University collaborators on this project are Peter Rubin of the Department of Plastic Surgery; William Wagner of the McGowan Institute for Regenerative Medicine, and Thomas Gleason of the Department of Cardiothoracic Surgery.

The research was supported by NIH.

Mind-controlled robot arm study receives Top 10 award

A project underway at the School of Medicine and UPMC in which a woman with quadriplegia took a bite of chocolate using a robot arm she controlled with her thoughts has been selected to receive one of the Clinical Research Forum’s Annual Top 10 Clinical Research Achievement Awards.

The awards recognize research teams that, in 2012, published compelling examples of the scientific innovation that results from the nation’s investment in clinical research that can benefit human health and welfare, according to the Clinical Research Forum (CRF).

Jennifer Collinger, faculty member in physical medicine and rehabilitation (PM&R), research scientist for the Pittsburgh VA Healthcare System and lead author of the brain computer interface study that was published in Lancet in December, presented the team’s work during the CRF annual meeting last month.

Said Collinger: “The team, which includes participant Jan Scheuermann, believes that the hard work we are doing now could one day help people with disabilities attain better function and greater independence.”

Added Steven Reis, associate vice chancellor for clinical research, Health Sciences, and director of the Clinical and Translational Science Institute, who nominated the project for award consideration: “This breakthrough will provide opportunities for paralyzed individuals to interact in meaningful ways with their environments by using brain commands to control dexterous robotic prosthetic limbs. Also, it serves as a paradigm for high-impact translational research conducted by a multidisciplinary team.”

University co-authors of the paper included senior authors Andrew Schwartz in the Department of Neurobiology; Michael Boninger, chair of PM&R and director of UPMC Rehabilitation Institute; Elizabeth Tyler-Kabara in the Department of Neurological Surgery; Angus J. McMorland and Meel Velliste of the Department of Neurobiology; Brian Wodlinger, John E. Downey and Wei Wang of PM&R, and Doug Weber of the Department of Bioengineering in the Swanson School of Engineering.

The CRF is an organization comprised of the nation’s top academic medical centers and health-care systems whose goal is to sustain and expand a cadre of talented, well-trained clinical investigators at all stages of career development, and support nurturing environments and comprehensive research capabilities within academic institutions. Its mission is to provide leadership to the national clinical and translational research enterprise and promote understanding and support for clinical research and its impact on health.

Recipe found for making large numbers of stem cells

Stem cells and tissue-specific cells can be grown in abundance from mature mammalian cells simply by blocking a certain membrane protein, according to scientists at the School of Medicine and NIH. Their experiments also show that the process doesn’t require other kinds of cells or agents to artificially support cell growth and doesn’t activate cancer genes.

Scientists hope lab-grown stem cells and induced pluripotent stem (iPS) cells, which have the ability to produce specialized cells such as neurons and cardiac cells, could one day be used to treat diseases and repair damaged tissues.

Said study co-author Jeffrey S. Isenberg, faculty member in the Division of Pulmonary, Allergy and Critical Care Medicine in the School of Medicine: “Even though stem cells are able to self-renew, they are quite challenging to grow in the lab. Often you have to use feeder cells or introduce viral vectors to artificially create the conditions needed for these cells to survive and thrive.”

In 2008, Isenberg was working in the National Cancer Institute (NCI) lab of senior author David D. Roberts using agents that block a membrane protein called CD47 to explore their effects on blood vessels. He noticed that when cells from the lining of the lungs, called endothelium, had been treated with a CD47 blocker, they stayed healthy and maintained their growth and function for months.

Roberts’s NIH team continued to experiment with CD47 blockade, focusing on defining the underlying molecular mechanisms that control cell growth. They found that endothelial cells obtained from mice lacking CD47 multiplied readily and thrived in a culture dish, unlike those from control mice.

Another member of the team discovered that this resulted from increased expression of four genes that are regarded to be essential for formation of iPS cells. When placed into a defined growth medium, cells lacking CD47 spontaneously formed clusters characteristic of iPS cells. By then introducing various growth factors into the culture medium, these cells could be directed to become cells of other tissue types. Despite their vigorous growth, they didn’t form tumors when injected into mice, a major disadvantage when using existing iPS cells.

Said Isenberg: “These experiments indicate that we can take a primary human or other mammalian cell, even a mature adult cell, and by targeting CD47 turn on its pluripotent capability. We can get brain cells, liver cells, muscle cells and more. In the short term, they could be a boon for a variety of research questions in the lab.”

In the future, blocking CD47 might make it possible to generate large numbers of healthy cells for therapies, such as alternatives to conventional bone marrow transplantation and complex tissue and organ bioengineering, he added. The findings provide a rationale for using CD47-blocking therapies to increase stem cell uptake and survival in transplanted organs, matrix grafts or other applications.

Co-authors included researchers from NCI; George Washington University; the National Heart, Lung and Blood Institute; the National Human Genome Research Institute (NHGRI), and the National Institute of Allergy and Infectious Diseases.

The project was funded by Pitt’s Vascular Medicine Institute, NIH, NCI, NHGRI, the Institute for Transfusion Medicine and the Western Pennsylvania Hemophilia Center.

The research was reported in April in Scientific Reports.

Prof awarded electronic games research fellowship

Brian Beaton, faculty member in the School of Information Sciences, has been awarded a Strong Research Fellowship to conduct research at the International Center for the History of Electronic Games.

ICHEG holds one of the world’s largest collections of electronic games and game-related materials.

Beaton’s research aims to understand science-themed games from the early PC era as part of his work on citizen science and its precursors. He will investigate early electronic games that promoted scientific literacy, allowed players to engage in science-related tasks and simulated scientific work and workplaces. He also will investigate how early science-themed electronic games were designed and marketed.

Beaton also recently won a Gaming Research Fellowship from the Center for Gaming Research at the University of Nevada-Las Vegas. He will spend two weeks there conducting research into how the Las Vegas gaming industry draws crowds of players to specific games.

The larger purpose of Beaton’s research is to identify crowd-drawing techniques and strategies used in Las Vegas that may be effective in drawing people to online citizen science games.

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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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