Category: Medicine

Researchers at the University of Georgia have discovered two new drug targets to treat Acute Respiratory Distress Syndrome

AU/UGA Medical Partnership students headed to 17 states, institutions including Johns Hopkins and Harvard.

The Fellowship program emphasizes expertise in population and public health informatics

Drug helps prevent cognitive impairment following stroke in laboratory rats

Selected studies address primary care questions and recommend changes in practice that will improve patient outcomes

UGA researchers have found a technology that controls whether satellite cells replicate themselves or turn into muscle cells

UGA graduate, surgeon’s medical breakthroughs have been saving lives for more than 70 years

Non-invasive method could significantly reduce the toxic side effects of chemotherapy

Stephen Dalton is director of the Center for Molecular Medicine (CMM), founded in 2012 with a focus on translational research—taking basic research findings and converting them into therapies for human diseases, cures and diagnostics. The center moved this fall into a new $25 million, 43,000-square-foot-facility that will house newly hired faculty and up to 10 research groups. Dalton, professor and Georgia Research Alliance Eminent Scholar of Molecular Cell Biology, discusses the importance of translational research, the state of stem cell research and the biggest problem faced by scientists.

What is molecular medicine?

Molecular medicine is quite a broad topic, but what it really means is taking our understanding of cell structure and cell function at the molecular level, and using that information to try and generate new therapies, which themselves are often molecular. It’s really a reflection of both the molecular level of research that’s being done, but also the therapeutic solutions that will arise from the research—new medicines, new drugs, new vaccines. Every researcher in the center will have a direct interest in curing and understanding at least one type of disease, whether that be neurological, such as Parkinson’s and Alzheimer’s and dementia, or cardiovascular, such as heart disease and stroke, or metabolic, such as diabetes.

What do you find appealing about translational research?

I think doing basic research is intellectually stimulating, but I think that at the back of everyone’s mind is making an impact on society and supporting UGA’s broader mission, which is to help the community and to provide solutions. I think that’s important. We can’t just ask intellectually interesting questions for the sake of it—there has to be an endpoint and some utility and value for the community. The way that I like to see science working is for researchers to do great, cutting-edge basic science, but then take the findings of those experiments and apply them for the greater good.

Will CMM researchers be working with stem cells?

That’s going to be an important part of it, but it’s not the only iron in the fire. You need to use multiple research models to really understand complex biological questions and then develop therapies and cures. You need to use animals to understand disease progression, so there are going to be mouse models. We’ll also be doing things like drug screens—looking for new drugs that can help cure diseases. And we’ll be developing new diagnostic techniques to help us better understand diseases and develop therapies.

Last year marked the 10th anniversary of the discovery of induced pluripotent stem (iPS) cells. What kind of impact has that had?

The introduction of iPS cells—cells that are generated directly from adult cells—has really transformed the stem cell field in many ways. It’s removed the ethical problem of working with pluripotent cells—undifferentiated cells that have the ability to differentiate into specialized cells—because previously they were derived from embryos.

There are a number of different ways that you can use iPS cells and pluripotent cells for drug screening and therapies. One is for transplantation into a patient. There are some clinical trials underway where you can take iPS pancreatic cells and transplant them into people with type 1 diabetes, where they produce insulin and help control glucose levels in the bloodstream. That’s very promising. There are also trials for using iPS cells to treat macular degeneration and Parkinson’s disease. I expect there will be more and more such applications over the next five to 10 years. There’ll also be therapies designed for a number of blood disorders, such as sickle cell disease.

However, I think the biggest impact these stem cell models will have is in drug discovery for the development of new therapeutics, as they provide a plentiful source of patient-derived cells to screen or test experimental drugs. I expect that it will have a massive impact over the next decade.

What challenges do you anticipate during the center’s first decade?

The big problem that all researchers face now, and probably for the next 10 years, is the tightness of the budgets coming from the federal government, whether it be the National Institutes of Health or the National Science Foundation. Budget lines are a real concern because that’s the lifeblood of research—getting the funding to hire graduate students, postdoctoral fellows and technicians to push the program forward. Fortunately, the people we’re hiring are really top notch, and we anticipate they’re going to be competitive. But it is always a worry when you hear less-than-positive things about funding levels.

A computer model developed by researchers could lead to improved treatment protocols

A new drug target for the two most common types of myeloid leukemia—including a way to turn back the most aggressive form of the disease—has been identified by a research team including UGA’s Takahiro Ito and collaborators at the University of Tokyo.

By blocking a protein called BCAT1, the researchers were able to stop cancer cell growth in mice and human blood samples from leukemia patients.

The BCAT1 protein activates the metabolism of a group of amino acids known as branched-chain amino acids, or BCAAs, which are essential building blocks of proteins in all cells and thus necessary for aggressive leukemia cells to grow. The same enzymes also are responsible for the development of brain and lung tumors.

Earlier research indicated that BCAT breaks down the BCAAs in most healthy tissues. The new paper, published in the journal Nature, shows for the first time that rather than breaking them down, leukemia cells use the BCAT1 pathway to produce BCAAs. By blocking the protein, researchers can reverse the disease’s aggressiveness.

“We wanted to understand what is driving aggressiveness in acute leukemia, and then examine whether targeting such a pathway would reverse the disease back to the treatable phase,” said Ito, senior author on the paper and assistant professor of biochemistry and molecular biology in the Franklin College of Arts and Sciences.

This brief appeared in the fall 2017 issue of Research Magazine. The original press release is available at http://news.uga.edu/releases/article/researchers-harness-metabolism-to-reverse-aggressiveness-in-leukemia/.

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Medical marijuana is having a positive impact on the bottom line of Medicare’s prescription drug benefit program in states that have legalized its use for medicinal purposes, according to a study led by UGA researchers.

Researchers at UGA have created a new therapeutic for prostate cancer that has shown great efficacy in mouse models of the disease.

Many patients who see physicians for sinus infections expect to be prescribed an antibiotic, but for the majority of them, that course of treatment won’t be effective because their infections aren’t caused by bacteria.

Folates can stimulate stem cell proliferation independently of their role as vitamins, according to a collaborative study from the University of Georgia and Tufts University, which used an in vitro culture and animal model system in their findings.

By Lori Johnston (This article originally appeared in the June 2016 issue of Georgia Magazine)

Luke Mortensen’s mission is to find a way to replace missing bones in children and save lives.

Mortensen finished a postdoctoral fellowship at Harvard Medical School in fall 2014 and joined UGA’s Regenerative Bioscience Center (RBC), which links researchers and resources in various disciplines to develop cures for human and animal diseases.

The center, established a decade ago by Steven Stice, offered Mortensen access to regenerative medicine and stem cell experts and a supportive, collaborative environment. A unit of the Office of the Vice President for Research, the center has grown to include more than 30 faculty from several UGA colleges and joint efforts with the Georgia Institute of Technology, Emory University and other research universities.

On the third floor of the RBC, located on East Campus, Mortensen built a novel laser microscope, the first major component of his new lab. He wanted to use his experience in microscopes and stem cells and interest in bone regeneration in a meaningful way-specifically, to find a treatment for hypophosphatasia (HPP), a rare congenital bone disease in which bones don’t mineralize or grow properly. The condition can cause stillbirth; for those who survive, bones are softer and more likely to fracture.

“I wanted to do something where I could use those key elements that I’d gathered as I went along, and try to apply it to something where it could impact people,” says Mortensen, an assistant professor with a joint appointment in the College of Agricultural and Environmental Sciences (CAES) and the College of Engineering.

His research could result in using stem cell therapy to permanently heal individuals with HPP. Earlier this year, he began using his two photon laser microscopes to visualize living cells inside of the bone and to track the cells within the bone marrow of mice.

“We’re starting from the ground up. That was really exciting. You could see the cells zipping around,” Mortensen says. “Getting to this point was sort of an adventure.”

The ultimate goal is to replace the damaged stem cells of someone who has a genetic defect with ones that are healthy and can permanently heal them, he says.

Bone regeneration, traumatic brain injury, and the first and only stroke model using swine in the U.S. are just some of the research areas at the RBC. Faculty members include biochemists, veterinarians, pharmacologists, toxicologists and animal scientists representing the CAES, the College of Education, the College of Engineering, the College of Public Health, the College of Pharmacy, the College of Veterinary Medicine and the Franklin College of Arts and Sciences.

RBC members also have received federal research grants and funding from government, public and private entities including the National Institutes of Health, the Bill and Melinda Gates Foundation, the American Heart Association, the Environmental Protection Agency and the Department of Defense. Nearly $7.6 million in grants were awarded to RBC members in 2014-15.

UGA’s expertise in fields such as regenerative medicine and veterinary medicine, combined with partnerships with Emory and Georgia Tech, gives the RBC a strong presence at industry and international meetings. The RBC provides training and education to researchers from around the world, and research findings and papers have appeared in more than 1,000 journals and publications. In RBC’s first 10 years, it has licensed technology and products, and Stice expects that commercialization efforts will grow.

No cold calling

Friendly and warm aren’t typically words used to describe laboratories, but they frequently come up in conversations with RBC members. The RBC was created in 2005 to lay a foundation to share resources, offer training and foster collaborative research across disciplines and institutions.

In 2008, the RBC was refocused on regenerative medicine and stem cell therapy, which was becoming a more recognized area of study internationally. Stem cells are “blank” cells that can develop into any type of cell. They can be manipulated into becoming specialized cells to treat specific conditions — heart muscle cells, for example, that can be injected into a person with heart disease. RBC researchers work primarily with adult stem cells, which come from a variety of sources such as skin, teeth and muscle as well as induced pluripotent stem cells that have been genetically reprogrammed.

Since refocusing on regenerative medicine, the RBC has grown and now includes 34 faculty members, 19 postdoctoral research assistants, more than 40 graduate students, and approximately 75 undergraduate students.

“What we’ve been able to do over the years is bring in faculty from a number of different colleges, including the vet school, where a lot of regenerative medicine is being done today,” says Stice, a D.W. Brooks Distinguished Professor in CAES and Georgia Research Alliance Eminent Scholar endowed chair.

RBC has recruited top researchers and offers the opportunity for new UGA faculty to become involved. Emerging efforts include a project involving cell manufacturing with GRA Eminent Scholar Art Edison and the new Marcus Center for Therapeutic Cell Characterization and Manufacturing at Georgia Tech.

“What it’s taken to grow is really the opportunity to be able to recruit faculty directly to the center. Some of the most productive research going on at the university is going on in our better-organized centers and institutes,” says David Lee, UGA’s vice president for research.

Three years ago, UGA, Georgia Tech and Emory formed Regenerative Engineering and Medicine, a research center that seeks to establish the state as a national leader in regenerative clinical therapies. The collaboration also awards seed grants to fund work among the institutions.

“We’ve been able to bring different groups, different schools and different disciplines together and obtain funding,” Stice says. “The progress toward therapies is never as fast as I’d like it to be, although we’ve made progress and we’ve contributed to that area.”

The RBC’s interdisciplinary approach brings together faculty and researchers who might not otherwise connect, even if their offices are on the same side of campus. The RBC facilitates introductions that otherwise might feel like a cold call, says Franklin West, RBC member and CAES assistant professor. For example, he and Susan Fagan, Albert W. Jowdy Professor and associate department head of clinical and administrative pharmacy in the College of Pharmacy, attended the American Heart Association’s International Stroke Conference.

“The fact that these researchers are world-renowned experts means they’re in high demand. By having this group, we’re able to get the attention from an elite circle,” says West, whose research focuses on stroke and traumatic brain injury.

New ideas and a broader, fresh perspective can emerge from those collegial meetings and RBC events, says Maria M. Viveiros, assistant professor in the College of Veterinary Medicine. Viveiros and associate professor Rabindranath De La Fuente are studying reproductive health and how chromosomes behave and break, which can lead to genetic disorders such as Down syndrome. Their research could lead to noninvasive strategies in early prenatal care and maternal health.

When they learned about a super-resolution microscope custom-made by researchers with the College of Engineering (who were located next door), the RBC provided a natural way to connect and develop pilot experiments to look at DNA sequences in a 3D structure. The level of resolution was not possible five years ago and is a major breakthrough, De La Fuente says.

“We can break new ground in these areas and come up with completely new information,” he says. “That has been a really important example of how the RBC has been a good center that has actually integrated all these different researchers and facilitated these kinds of interactions.”

“It’s valuable access to a lot of people who are doing some very interesting things, and all of a sudden you find yourself across the table from them,” Viveiros says. “It just fosters these very easy conversations.”

Collaborating with curious students

The RBC Fellows program has grown to 78 undergraduate students, up from 50 in the 2014-15 academic year. Students can immerse themselves in research and lab work at the RBC, where they hone critical thinking, present at scientific summits off campus and publish their work.

The RBC has helped produce Goldwater Scholarship winners, as well as Gates and Udall winners, and several Goldwater, Truman, Gates and Udall nominees. In 2016, three nominees for prestigious scholarships-two Goldwater nominees and one Truman nominee-were RBC fellows.

“I don’t think I would’ve been selected as a nominee or even had a chance to apply, if I had not had my experience at the RBC,” says Hannah Mason. The UGA junior, who’s pursuing bachelor’s degrees in molecular biology and Spanish, was nominated for a 2016 Goldwater Scholarship and received an honorable mention.

Through their RBC connections and work, students spend their summers working with researchers at other institutions, such as the Massachusetts Institute of Technology (MIT) and Duke University.

“There’s no doubt in my mind that had I not had this research experience, and especially the research experience last summer (at MIT), I would not have even been considered,” says Cali Callaway, a junior pursuing a dual BS/MS in biology and artificial intelligence, who received a 2016 Goldwater Scholarship. “It really does require that you’ve done research, and done it in a substantial way, which is exactly what I’ve had the opportunity to do here.”

About 50 graduate students work at the RBC, a number Stice would like to double in the next three years.

What’s next?

The center will continue to build partnerships with industry and foundations, work strategically with other entities, including research universities outside of the state, and move innovations to the marketplace, Lee says. One RBC start-up, Cytogenesis, acquired by Viacyte, is now in clinical trials for diabetes. Stice has founded four biotechnology companies at UGA. One of those, ArunA Biomedical, provides cells to groups involved in cell therapy, particularly in the area of stroke, and it was the first company to commercialize a product that helped lead to approval of new cognitive-enhancing drugs.

Larger pharmaceutical companies are expressing great interest in this area and are starting to provide the resources to start large cell manufacturing for cell therapy, Stice says. Developing immunotherapies that use an individual’s stem cells to attack cancer in their body is one way the RBC can play a large role in commercialization.

“There are strong opportunities for Georgia to carve out a niche in stem cell medical manufacturing and transportation,” Stice says.

Another burgeoning area that stands to set the RBC apart is the development of new animal models for studies of human diseases, according to Lee. The swine stroke model was developed by a team that includes West plus RBC and vet med faculty members Simon Platt, a neurosurgeon and professor focusing on canine stroke and brain tumors; Shannon Holmes, assistant professor of advanced imaging; and Elizabeth “Buffy” Howerth, a professor of cellular and molecular pathology of disease.

“The RBC is critical to the effort. It helped me get into contact with other individuals who are like-minded and had interest in doing the stroke model,” says West. “It’s not that it would take longer. In some cases, it wouldn’t happen at all.”

May 10, 2016

A sad reality for many women battling ovarian cancer is that they will likely endure treatment more than once. The disease has a high rate of recurrence, and when it does return, it has often developed resistance to chemotherapy.

But researchers at UGA may have found a reason why this happens. College of Pharmacy associate professors Mandi Murph and Shelley Hooks have shown that a protein called RGS10 can impact the effectiveness of ovarian chemotherapy in the laboratory.

“Chemoresistance to ovarian cancer is what kills women,” Hooks said. “It’s the deadliest gynecologic cancer. Most women with ovarian cancer will have their tumors come back.”

“Within two years, 85 percent of women will have their cancer come back in a more aggressive form,” Murph said. “It is during that time that they won’t respond to the chemotherapy.”

Although it’s too soon to tell, their discovery could alter future treatment strategies. For now, it solves a puzzling observation they originally made about RGS10 years ago.

Their paper, “Cellular deficiency in the RGS10 protein facilitates chemoresistant ovarian cancer,” reviews over five years’ worth of research on RGS10 and was published in the journal Future Medicinal Chemistry.

“RGS10 is basically an off switch. It does very little,” Murph said. “However, it’s important because when it gets turned off, cells become resistant to chemotherapy.”

In previous studies, Hooks and Murph tested cells to see how they would react to common chemotherapy medicines. They were able to manipulate the sensitivity of ovarian cancer cells to common chemotherapy treatments like paclitaxel, cisplatin and vincristine by changing RGS10 expression.

“Depending on the expression levels of RGS10, the chemotherapy for ovarian cancer is more or less effective,” Hooks explained. “If there were a way to reverse silencing of the RGS10 protein, then we could potentially restore sensitivity to drugs.” The Hooks lab is currently working to screen libraries of compounds to identify molecules that may restore RGS10 expression in cells.

Murph also discovered that mTOR signaling is enhanced by the loss of RGS10 expression.
“mTOR essentially determines the survival of [cells], which in turn indicates whether chemotherapy will be sufficient to kill the cells,” she said. “It’s exciting to have found this piece of the puzzle.”

Murph recommends more research on mTOR inhibitors to see how they can be combined with traditional chemotherapy to reduce resistance among cells.

Currently, platinum chemotherapy drugs, like paclitaxel and carboplatin are used as a one-size-fits-all treatment for ovarian cancer patients. However, chemoresistance to platinum drugs remains a serious challenge to curing ovarian cancer.

“Five years ago, this field of RGS10 cancer research didn’t exist,” said Murph. “But Dr. Hooks and I have been able to create this area of research and lead it. Before no one knew or cared about RGS10 effects in cancer cells. Now we have more research that could contribute to improving chemotherapy.”

By Molly Berg

Resistance to chemotherapy is a major problem for those suffering from ovarian cancer. University of Georgia researchers are giving patients new hope with recent findings that help pinpoint the mechanisms causing chemoresistance.

Over the last five years, UGA College of Pharmacy associate professors Mandi Murph and Shelley Hooks have discovered that a type of protein known as RGS10 impacts the effectiveness of ovarian cancer chemotherapy. Murph also discovered that mTOR signaling, a protein encoded by the mTOR gene, drives the effects of RGS10.

Resistance to chemotherapy that was previously very effective is a major roadblock that prevents better outcomes in this disease. Finding mTOR as the mechanism of RGS10’s effects could help explain the unique features of chemoresistant cancer cells.

“Chemoresistance to ovarian cancer is what kills women,” Hooks said. “It’s the deadliest gynecologic cancer. Most women with ovarian cancer will have their tumors come back.”

“Within two years, 85 percent of women will have their cancer come back in a more aggressive form,” Murph said. “It is during that time that they won’t respond to the chemotherapy.”

Their article, “Cellular deficiency in the RGS10 protein facilitates chemoresistant ovarian cancer,” reviews over five years worth of research on RGS10 and was published in Future Medicinal Chemistry.

Their findings on RGS10 have jump-started an interest in the protein as well as created several major research articles on the topic.

“RGS10 is basically an off switch. It does very little,” Murph said. “However, it’s important because when it gets turned off, a person will become resistant to chemotherapy.

“mTOR essentially determines the survival of [cells], which in turn indicates whether chemotherapy will be successful. It’s exciting to have found this piece of the puzzle.”

In their past articles, Hooks and Murph tested cells to see how they would react to common chemotherapy medicines. They were able to manipulate the sensitivity of ovarian cancer cells to common chemotherapy treatments like paclitaxel, cisplatin and vincristine by changing RGS10 expression.

“Depending on the expression levels of RGS10, the chemotherapy for ovarian cancer is more or less effective,” Hooks explained. They also found that RGS10 is epigenetically silenced, meaning that the protein is turned off due to external or environmental factors and not genetics.

“If there were a way to reverse silencing of the RGS10 protein, then we could potentially restore sensitivity to drugs,” she explained. “It would mean a better chance of survival for women with ovarian cancer.”

While RGS10 is responsible for chemoresistance, it could also be the key to improving treatment of chemotherapy.

“Chemoresistance prevents us from curing the disease,” Murph said. “If we can cure chemoresistance, we can cure ovarian cancer.”

Currently, platinum chemotherapy drugs, like paclitaxel and carboplatin are used as a one-size-fits-all treatment for ovarian cancer patients. However, chemoresistance to platinum drugs remains a serious challenge to curing ovarian cancer.

Murph recommends more research on mTOR inhibitors to see how they can be modified to respond to chemotherapy.

“Five years ago, this field of RGS10 cancer research didn’t exist,” she said. “But Dr. Hooks and I have been able to create this area of research and lead it. Before no one knew or cared about RGS10 effects in cancer cells. Now we have more research that could contribute to improving chemotherapy.”

To read more about Hooks’ and Murph’s RGS10 protein research, visitwww.ncbi.nlm.nih.gov/pubmed/26293348. To learn more about Murph’s mTOR signaling research, visit www.ncbi.nlm.nih.gov/pubmed/26319900.

The study was supported by the National Institutes of Health National Cancer Institute under grant numbers 1R15CA151006-01 and 1R15CA176653-01A1, a research scholar grant from the American Cancer Society, the Georgia Research Alliance and the Marsha Rivkin Center for Ovarian Cancer Research.

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