A receptor that is already a target for treating neurodegenerative disease also appears to play a key role in supporting the retina, scientists report.
Without sigma 1 receptor, the Müller cells that support the retina can’t seem to control their own levels of destructive oxidative stress, and consequently can’t properly support the millions of specialized neurons that enable us to transform light into images, scientists report in the journal Free Radical Biology and Medicine.
Without support, well-organized layers of retinal cells begin to disintegrate and vision is lost to diseases such as retinitis pigmentosa, diabetic retinopathy and glaucoma, said Dr. Sylvia Smith, retinal cell biologist and Chairwoman of the Department of Cellular Biology and Anatomy at the Medical College of Georgia at Georgia Regents University
The surprising finding makes the sigma 1 receptor a logical treatment target for these typically progressive and blinding retinal diseases, said Smith, the study’s corresponding author. It has implications as well for other major diseases, such as cardiovascular disease and cancer as well as neurodegenerative disease, where oxidative stress plays a role.
What most surprised the scientists was that simply removing sigma 1 receptor from Müller cells significantly increased levels of reactive oxygen species, or ROS, indicating the receptor’s direct role in the oxidative stress response, Smith said. They expected it would take them giving an oxidative stressor to increase ROS levels.
So they looked further at the sigma 1 receptor knockouts compared with normal mice, and found significantly decreased expression in the knockouts of several, well-known antioxidant genes and their proteins. Further examination showed a change in the usual stress response.
These genes that make natural antioxidants contain antioxidant response element, or ARE which, in the face of oxidative stress, gets activated by NRF2, a transcription factor that usually stays in the fluid part of the cell, or cytoplasm. NRF2 is considered one of the most important regulators of the expression of antioxidant molecules. Normally the protein KEAP1 keeps it essentially inactive in the cytoplasm until needed, then it moves to the cell nucleus where it can help mount a defense. “When you have oxidative stress, you want this,” Smith said of the stress response, which works the same throughout the body.
Deleting the sigma receptor in the Müller cells altered the desired response: NRF2 expression decreased while KEAP1 expression increased. The unhealthy bottom line was that ROS levels increased as well.
The study is believed to provide the first evidence of the direct impact of the sigma 1 receptor on the levels of NRF2 and KEAP1, the researchers write.
“We think we are beginning to understand the mechanism by which sigma 1 receptor may work and it may work because of its action on releasing antioxidant genes,” Smith said.
While the ubiquitous receptor was known to help protect neurons in the brain and eye, its impact on Müller cell function was previously unknown. The significant impact the MCG scientists have now found helps explain the dramatic change they documented after using pentazocine, a narcotic already used for pain relief, in animal models of both retinitis pigmentosa and diabetic retinopathy. Pentazocine, which binds to and activates the sigma 1 receptor, seems to preserve functional vision in these disease models by enabling many of the well-stratified layers of photoreceptor cells to survive.
Next steps include clarifying whether it’s actually preservation or regeneration of the essential cell layers and how long the effect lasts. “We do see some retention of function, that is clear and that I am very excited about,” Smith said.
Müller cells are major support cells for the retina, helping stabilize its complex, multi-layer structure, both horizontally and vertically; eliminating debris; and supporting the function and metabolism of its neurons and blood vessels. Typically bustling Müller cells can become even more activated when there is an insult to the eye, such as increased oxidative stress, and start forming scar tissue, which hinders rather than supports vision. Problems such as diabetes, can increase ROS levels.
ROS are molecules produced through normal body function such as breathing and cells using energy. The body needs a limited amount of ROS to carry out additional functions, such as cell signaling. Problems, from eye disease to cancer, result when the body’s natural system for eliminating excess ROS can’t keep up and ROS start to do harm, such as cell destruction.
Normally humans have about 125 million night-vision enabling rods intermingled with about 6 million cones that enable us to respond to light and see color.
The research was supported by the National Eye Institute and the James and Jean Culver Vision Discovery Institute at GRU. MCG Assistant Research Scientist Dr. Jing Wang is the study’s first author.
From an engineering standpoint, the skeleton is a work of art.
A multifaceted structure providing both support and protection, it handles everything from storing vital minerals to producing red blood cells, all while allowing us to move. But it does so much more than that. Our teeth, for example, grind food into a more readily digestible form, making it easier for us to draw in the nutrients we need to survive. Our hands, which combined contain 54 of the body’s 206 total bones, have developed into universal tools capable of clawing, plucking, grasping and crushing with substantial strength. Pound for pound, our bones are more durable than steel.
In a way, the human skeleton is something of a dream machine.
Unfortunately, though, even the greatest machines break down.
Dr. Meghan McGee-Lawrence, an assistant professor in the Medical College of Georgia’s Department of Cellular Biology and Anatomy, has built a career on the back of skeletal research. Recently, she and a team of researchers headed by Colorado State University’s Dr. Seth Donahue, may have discovered something to help keep that machine running a little more smoothly.
The secret? Sleeping black bears.
“Years ago, Seth started thinking about the effects of mechanical loading on bones,” said McGee-Lawrence, who began her research as one of Donahue’s lab assistants at Michigan Technological University. “He was interested in the mechanical response of bone tissue, because that’s his background – biomechanical engineering.”
Living and working in Michigan’s Upper Peninsula at the time, Donahue’s thoughts eventually led him and his team into the wild. More specifically, it led them to an animal – the common black bear.
“He started thinking about, well, what happens when a bear hibernates? It’s lying down; it’s sleeping for six months,” said McGee-Lawrence. “You’d expect that, if black bears had skeletons that worked like other animals, they’d lose bone during that time.”
Use it or lose it is an all-too-common concept, especially among scientists working with the skeleton. As a living system, our skeletons are in a constant state of flux. When bone tissue ages or becomes damaged, specialized cells known as osteoclasts dissolve it, returning calcium and other trace minerals to the body to be either repurposed or excreted. At the same time, new tissue is being generated by another specialized type of cell known as osteoblasts. In an ideal situation, the two cell types work in tandem, removing old tissue and replacing it at a similar rate.
That isn’t always the case, however.
Bone disorders such as osteoporosis and osteopenia occur when tissue is resorbed faster than it can be created – a condition that’s exacerbated by age and a prolonged lack of movement. After six months of rest, then, black bears should have been prime candidates for debilitating bone disorders.
But they weren’t.
“Nobody had ever really looked at that before,” said McGee-Lawrence. “There were a couple of random studies where people had said ‘bears probably don’t lose bone,’ but a real, thorough study hadn’t been done. So that’s where the project got started.”
McGee-Lawrence said the decision to work with bears was influenced partly by convenience, and partly by the uniqueness of the animal model.
“You’d be surprised how often I get questions about what hibernates and what doesn’t,” she said. “There are plenty of other hibernators. Bears are probably the largest, but you have some ground squirrels, some bats, that also hibernate.”
The problem is, smaller hibernators tend to be bad at hibernating.
“When a bear hibernates, they typically sleep for a period of months,” said McGee-Lawrence. “Some sleep a little less, but in the North, the average is around six months.”
During that time, the bear becomes a closed system; it does not eat, drink or excrete during hibernation, something smaller hibernators cannot do.
“Smaller hibernators, every couple of weeks they’ll raise their body temperature and wake up to eat, drink, excrete,” said McGee-Lawrence. “Then, after they’ve taken care of that, they’ll lower their temperature back down. There’s a significant metabolic difference between smaller hibernators and bears that was important to our research.”
Settled on studying bears, McGee-Lawrence and her team, headed by Donahue, reached out to an unlikely, but easy, source of samples. Meat processing plants.
“There’s a big fall hunting season in Michigan,” said McGee-Lawrence. “That’s where we got our first samples in the Upper Peninsula; we had easy access to bone samples by going around to meat processing plants and finding tissue from bears that had been killed by hunters.”
Then, after finding tissue to study the status of bone and tissue samples during the winter hibernation period, the research moved to Utah.
“There’s both a fall and a spring hunting season for bears in Utah,” she said. “You could find tissue samples in the spring from bears who had just come out of the den versus bears who were preparing to go into hibernation. It was a good starting point for figuring out what happens during hibernation.”
From there, however, there was only one place left to go for the research.
The team had to start studying live bears.
“Working with live bears was outstanding,” said McGee-Lawrence, smiling fondly over a picture of herself with a live, and sedated, black bear. “It’s as exciting as you’d expect.”
For the most part, McGee-Lawrence said she worked vicariously through other researchers a lot of the time, receiving bone and tissue samples that were sent back to the lab. On a few special occasions, though, she went straight to the source.
“I got a chance to go to Utah, where they were tracking radio-collared bears,” she said. “We got to go out and track them, which was a very cool experience for me. I also had an opportunity to go to Washington, where we studied captive grizzlies. That time, I actually went in and collected the samples myself.”
Despite the mental images conjured by the thought of working with live bears, McGee-Lawrence said the danger was minimal. While she and her team were performing research, other scientists were studying the same animals, and always with a handler.
“Anytime you’re studying a unique animal model, like a bear, that’s in short supply, you want to make the most use of the study,” she said. “It’s not like we were just studying bone. There were also people there studying the cardiac system and the muscles, so we always had a team around. And there was always somebody there who was very well-prepared to deal with a large animal model.”
She stressed that the animals her team worked with were always safely anesthetized.
After working with live bears and taking yet more samples, McGee-Lawrence and her team made a fascinating discovery. Over the course of hibernation, their subjects had lost and gained virtually no bone density. Six months of rest had almost no effect whatsoever on the strength of the bears’ bones.
McGee-Lawrence, led by Donahue and assisted by four other authors, published their findings in the July issue of The Journal of Experimental Biology. Since then, their article, titled “Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation,” has received global attention.
According to McGee-Lawrence, Donahue and the team immediately understood what they’d found. An animal that can sit still for six months, unfazed by the negative effects of bone resorption, could be extremely beneficial for understanding how the body regulates bone loss.
But the team’s research won’t stop there.
“Once we found out that the bears didn’t lose bone when they hibernated, that meant something was unique about them,” said McGee-Lawrence. “The natural next question was, ‘How can we use that for humans?’”
From a medical perspective, surely the sky must be the limit, right? Aim a little higher, said McGee-Lawrence.
“All the cells in your skeleton are used to being weighed down by gravitational forces and mechanical forces from walking and running, things like that,” she said. “Who doesn’t deal with that? Astronauts. As soon as an astronaut goes up into space, all of those loads are gone.”
While that kind of weightlessness might seem like a dream to some, the damage it does to our bones is detrimental.
“Because bone is such an important mechanical tissue, bone cells maintain bone mass in proportion to the loads that it experiences,” she said. “When those loads are gone, the skeletal cells are going to sense that and get rid of some of that skeletal mass.”
And they get rid of a lot, sometimes up to as much as two percent per month spent in space. That kind of wear and tear makes lengthy space flights, like the proposed missions to Mars, nearly impossible. Because of this, McGee-Lawrence said, astronauts join the list alongside partially paralyzed and osteoporotic patients as potential beneficiaries of her team’s research.
She said current treatments, while somewhat effective, just aren’t cutting it.
“As you can imagine, NASA doesn’t want a bunch of osteoporotic astronauts, so they have therapies in place,” she said. “They have vacuum treadmills, where the astronaut is literally vacuumed down into a self-contained treadmill, and they have a lot of resistance bands. But those treatments just aren’t that reliable. It’s exciting to think about how that could change in the coming years.”
Speaking of change, McGee-Lawrence said the next step for her team’s research seems clear.
“What we did in the current paper was figure out how different proteins and enzymes affect bone, how they change over the course of hibernation,” she said. “The next step is figuring out how those things are changing. Ultimately, we want to understand, when a bear hibernates, how is it controlling bone mass? We haven’t answered that. We know they don’t lose bone, and we know how a number of things that affect bone are changing. But we don’t know the next level up from that – ultimately, what’s regulating it.”
Thankfully, based on previous hibernation studies, the team has a good foundation to work from. At present, the likeliest culprit for bear bone preservation is the hypothalamus, the part of the brain that regulates temperature, hunger, thirst and other biological processes in humans.
“We know from other researchers that hibernation is controlled by the hypothalamus, so it’s probably some central mechanism that not only helps to preserve the skeleton, but also helps to regulate energy conservation and all of these other biological changes,” said McGee-Lawrence.
Regardless of where their research takes them, however, McGee-Lawrence said her team is looking forward to the endgame – treating serious bone disorders.
“Even if what’s happening in the bears is regulated by the brain and isn’t something that can be replicated exactly in an astronaut or an osteoporotic patient, if you can figure out kind of that intermediate step between the central control and what’s affecting the skeleton, you can narrow in on maybe a protein that could be turned into a drug therapy.”
And that, McGee-Lawrence said, is the market of the future.
Dr. Mark W. Hamrick has resigned his role as Senior Vice President for Research effective Sept. 1 and will return to the Department of Cellular Biology & Anatomy to focus on research into bone biology.
“While it is a loss for us to lose Mark in this administrative role, we are grateful that his contributions to GRU’s research enterprise will continue,” said Dr. Gretchen B. Caughman, Executive Vice President for Academic Affairs and Provost. “He has worked tirelessly to advance research at GRU, and his accomplishments have included overhauling the intramural grants program, launching the Institute for Regenerative & Reparative Medicine, and organizing the first Augusta Research Symposium on Advances in Warrior Care. Mark is an outstanding colleague, and I look forward to his continued scientific contributions.”
Dr. Michael Diamond, Vice President of Clinical and Translational Sciences and Chair of the Department of Obstetrics and Gynecology at the Medical College of Georgia, will serve as Interim Senior Vice President for Research.
Hamrick became Interim Vice President for Research in 2010 and was named to the position permanently in 2011. His research in improving bone strength is funded by the National Institutes of Health and the U.S. Department of the Army.
As Senior Vice President for Research, he oversees all aspects of the university’s research enterprise, including developing a strategic plan to advance GRU’s goals related to sponsored research programs.
Hamrick received GRU’s 2009 Innovation in Teaching Award, 2009 and 2010 Exemplary Teaching Awards, and 2005 Outstanding Young Faculty Award in Basic Sciences. In his role at GRU, he has also provided administrative oversight to implement the new electronic platforms for research administration and recruited new leadership in the Office of Innovation Commercialization, clinical research, and Laboratory Animal Services. He developed new research communications, Research Impact and GResearch, with the Office of Communications and Marketing, and established new, collaborative research partnerships with the Savannah River National Lab and Georgia Tech.
“I am grateful for the opportunity to have led one of this university’s most critical missions,” Hamrick said. “It has been an honor to serve the hundreds of scientists here, who I truly believe are making a significant impact and lessening the burden of illness on our society with their important work.”
Postdoctoral fellows, medical residents and graduate students at Georgia Regents University will present their research at the 29th annual Graduate Research Day March 21-22.
Postdoctoral fellows, organized by Dr. Wendy Bollag, Professor of Cellular Biology and Graduate Studies, will discuss their research March 21 from 1-4 p.m. in room 2109 of the Interdisciplinary Research Building. Students and fellows will present posters March 22 from 10 a.m. to noon in the Wellness Center.
The day gives students an opportunity to get feedback on their work and offers an opportunity for them to sharpen their presentation skills before they present at national meetings, says Dr. Michael Brands, Professor of Physiology and Graduate Studies and Graduate Research Day coordinator.
Dr. Shu Chien, a Professor of Bioengineering and Medicine and Director of the Institute of Engineering in Medicine at the University of California, San Diego will speak about “Career Development: A Case History and General Thoughts” as the event’s keynote speaker Friday, March 22 at 12:30 p.m. in room 1103 of the Hamilton Wing of the Sanders Research and Education Building. Chien is a world leader in molecular, cellular and integrative studies on bioengineering and physiology in health and disease. In 2011 he was awarded the National Medal of Science from President Barack Obama, the highest honor for scientists and engineers in the country.
Dr. Mitchell Watsky, the former Associate Dean for Graduate Studies at the University of Tennessee Health Science Center, has been named Dean of the College of Graduate Studies at Georgia Regents University. He will assume his new role June 1.
In addition to his role as Dean, Watsky will join the faculty as Professor of Cellular Biology and Anatomy in the Medical College of Georgia, where he will continue to direct his research program, which includes several grants from the National Institutes of Health to investigate corneal wound healing.
“Dr. Watsky’s passion and experience as a teacher, mentor, researcher and administrator are precisely what we hoped to find in a Graduate Studies Dean,” said Dr. Gretchen Caughman, GRU Executive Vice President for Academic Affairs and Provost. “I am very grateful to Drs. Sylvia Smith and Ed Inscho for their respective service as the Interim Dean and diligent oversight of the graduate school, and to Drs. Patricia Cameron and Mike Brands for their tireless efforts as they assumed additional responsibilities to ensure that the College is on solid footing for success and growth.”
As associate dean at UT, Watsky successfully oversaw a comprehensive reorganization of their Interdisciplinary Basic Sciences Program. He focused on coordinating the graduate programs run out of the College of Medicine, which in addition to the Interdisciplinary Basic Sciences Program, include Biomedical Engineering and Imaging and the Masters of Pharmacology and Masters of Epidemiology Programs. He was also charged with coordinating and growing the university’s graduate program with St. Jude Children’s Research Hospital.
Watsky earned his doctorate in physiology at the Medical College of Wisconsin and completed a postdoctoral fellowship in physiology and biophysics at the Mayo Foundation in Rochester, Minn. He holds a patent as a co-inventor for the artificial cornea and an extensive portfolio of research, teaching experience and publications. He received the Silver Fellow Award from the Association for Research in Vision and Ophthalmology in 2010. In addition to ARVO, he is a member of the American Association for the Advancement of Science and the American Physiological Society.