FROM THE VICE PRESIDENT
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LOST LEWIS AND CLARK
Sidebar: Neurons get their close-up
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Vision is published annually by The University of Montana Office of the Vice President for Research and Development and University Relations. It is printed by UM Printing & Graphic Services.
PUBLISHER: Daniel J. Dwyer. MANAGING EDITOR AND GRAPHIC DESIGNER: Cary Shimek. PHOTOGRAPHER: Todd Goodrich. CONTRIBUTING EDITORS: Brianne Burrowes, Brenda Day, Judy Fredenberg, Joan Melcher, Rita Munzenrider, Patia Stephens and Alex Strickland. WEB DESIGN: Patia Stephens. EDITORIAL OFFICE: University Relations, Brantly Hall 330, Missoula, MT 59812, 406-243-5914. MANAGEMENT: Judy Fredenberg, Office of the Vice President for Research and Development, 116 Main Hall, Missoula, MT 59812, 406-243-6670.
Mind Under a Microscope
Neuroscience center reveals inner workings of the brain
By Cary Shimek
Few people would ever suspect cutting-edge gene therapy, 3-D cellular imaging, laser-based fluorescent spectroscopy and computational drug design to be going on in a remote mountain valley nestled away in Western Montana.
But that’s the case with UM’s Center for Structural and Functional Neuroscience, where Montana researchers use hard science and teamwork to unravel what happens inside the human brain, such as how neurons normally communicate and how these processes are disrupted by neurological diseases.
“We have two big focus areas,” center Director Rich Bridges says. “The first — typical of most neuroscience programs — is studying basic brain functions such as neurotransmitter metabolism, transport and signaling. Then we have our medicinal chemistry group, which builds molecules that we can use as tools to study various brain processes.”
Sidebar: Neurons get their closeup
Bridges says the neuroscience center got rolling in 1995 with the help of an IDeA (Institutional Development Award) program grant from the National Institutes of Health. This starter award was used to land two much larger grants from the National Center for Research Resources, growing the UM-based neuroscience program into a nationally competitive Center for Biomedical Research Excellence (COBRE).
Bridges says the neuroscience center has attracted about $18 million in grants over the years, building Montana’s scientific infrastructure and allowing new hires. By 2007 the center had grown to include 19 faculty members — 14 at UM, two at Montana State University-Bozeman and three at McLaughlin Research Institute in Great Falls. UM researchers in the center are from the biomedical and pharmaceutical sciences department, chemistry department, math department and biological sciences division.
“The center has been the catalyst for a new Ph.D. program, undergraduate courses and, of course, the research effort, which is going full blast,” Bridges says.
COBRE programs often are paired with medical schools, which makes the UM center somewhat unique. Bridges says his group created a competitive niche by channeling the expertise and intellectual disciplines found on a campus without a medical school into neuroscience.
“Our center also provides a very interactive group that acts as a support system,” he says. “At meetings you present your ideas, you tear them apart and constructively criticize them. We also write papers together. It’s modeled somewhat on the workgroup concepts used in software design, where you have people in different disciplines who throw their expertise into the ring and hash out problems from different perspectives. And it’s been successful.”
Bridges says this collegial teamwork concept influenced the design of the 2007 addition to UM’s Skaggs Building, where instead of isolated individual labs, the scientists work in broad research bays accommodating more than one investigator. All students work together in a single support room, and shared equipment rooms sit on the periphery of the labs. It’s all intended to encourage collaboration.
“We are building an infrastructure here that brings with it all the benefits of doing research — the scholarship, training for students, the discovery,” Bridges says. “At the same time we are addressing very significant health care problems primarily related to mechanisms of neurological diseases.”
The neuroscience center focuses on basic sciences and the cellular and molecular mechanisms used by neurons in the brain to communicate with one another. Researchers study a minute realm where neurotransmitters flit messages across the tiny synaptic gaps between neurons, vesicles carry communication cargoes within cells, gossamer membranes are crossed and molecules bind to specific proteins.
When systems at this level go awry, maladies such as Alzheimer’s, epilepsy, mental illness or addiction can result. But if the center can unravel how the systems work and what goes wrong when diseases strike, it’s not unthinkable that new drugs and therapies are on the horizon.
Bridges says basic research often leads to something totally unexpected. For instance, while studying a specific glutamate transporter (glutamate is one of the most common neurotransmitters in the brain), his team found that it is more abundant in tumor cells. So if a drug containing trace levels of radioactivity can be developed to adhere to this particular transporter, it could be used to map tumors within the body, helping doctors determine tumor location and size or whether chemotherapy is working.
“Two years ago we didn’t know we would have a cancer project,” he says. “But that is the way real basic research is supposed to work. We are never quite sure where it’s going to lead, but if you do exciting high-quality research, it almost always takes you to someplace that is clinically very relevant.”
Professor Mike Kavanaugh, who studies the mechanisms involved in learning and memory, knows this only too well — especially when one of his graduate students made a new discovery while exploring the endocannabinoid system.
“Receptors have been discovered in the brain that bind the psychoactive constituents in cannabis,” he says. “After they were discovered, cannabinoid molecules, called endocannibinoids, also were found in the brain.”
Kavanaugh says these cannabinoid receptors are probably the most abundant receptors in the brain, “but we know very little about the normal functions of the endocannabinoid system.”
Building upon science of the past, he says, his graduate students found that this system may play previously unsuspected roles in learning and memory in young rats and mice. Can the same be said of humans?
Kavanaugh and Associate Professor Jesse Hay both were lured to UM by the collection of talent in the neuroscience center. Hay says most center researchers study how transmitters get transported into cells, but he focuses on the secretory pathway — the way various proteins are passed among different compartments within a cell. His specialty is the first step in this pathway, which traffics proteins from a membrane called the endoplasmic reticulum to another membrane called the Golgi apparatus. When cells can’t use their vesicles to cross this step, diseases such as cystic fibrosis and hereditary emphysema can result.
Sidebar: Core facility models molecules
Exemplifying the level of talent in the center, Hay recently collaborated with investigators at the Yale School of Medicine to discover that the common coat proteins on transport vesicles within cells do more than simply shape vesicles. They also act as a kind of marker that determines where the vesicle goes and what it interacts with.
Bridges says Kavanaugh and Hay are examples of faculty who concentrate their efforts more on brain function, while others in the medicinal chemistry arena are synthetic chemists who custom-design molecules to be used as tools to study function in normal brains, as well as disease.
Professor Sean Esslinger, has developed a first-generation compound that inhibits specific neuronal transporters, creating a tool to help the center study processes such as addiction and memory. Esslinger also has developed his own research program to study glutamine, the little-studied precursor to glutamate.
“We do basic research where there are lots of chemists involved who are developing new classes of compounds that could potentially result in drugs,” he says. “I think there are definitely economic-development opportunities to advance into off-campus companies.”
Professor Chuck Thompson, says center researchers actually build molecules in the laboratory atom by atom in an effort to trick the body into thinking it’s getting a neurotransmitter when it’s actually getting something else.
“This could be used for a possible therapy downstream,” Thompson says, “or it could be used in the laboratory to study how particular cells behave.”
Thompson’s Holy Grail would be discovering a molecule that blocks vesicles inside cells from receiving signals. This could reduce certain behaviors or stop toxic processes.
Center investigators use a variety of animal models to study neuron function — even living brain slices — and in the last year Thompson’s lab learned to transfer the genetic information of the brain proteins it studies into yeast. Since yeast are numerous and reproduce rapidly, thousands of new small molecules may be tested quickly, allowing the lab to cherry-pick the two or three compounds that may be useful.
Associate Professor John Gerdes studies the brain’s serotonin transporters, which are targets for antidepressant drugs. He also studies the norephenephrine transporter, which apparently has links to drug abuse and attention-deficit disorder.
His lab has designed radioactive tracer-containing drugs that bind to serotonin transporters and can be used to assess their function in patients using a technique called positron emission tomography. This will allow researchers to map where the proteins are that the drug binds to in the intact brain. This could reveal physiological differences between depressed populations and people who are not depressed.
Bridges says the center and its researchers have been successful because they use strong basic science to attack neuroscience questions.
“We also have a level of collegiality and interaction that is synergistic,” he says. “It’s a very rare environment to have that much trust and interaction among your colleagues. And the other thing is that it’s amazing to be able to do this out here in Montana. It makes it that much more special.”
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