UAB part of global study of breathing issues in Rett syndrome
by Bob Shepard December 16, 2016

December 16, 2016 Print Email

December 16, 2016

UAB will study a drug originally developed for Parkinson’s disease that may help reduce breath holding in patients with Rett syndrome.

RS7983 alan percy 2009 6Pediatric neurologist Alan Percy, M.D., is a leading clinician and researcher into Rett Syndrome Researchers at the University of Alabama at Birmingham are part of the international STARS study to see if a drug originally developed for Parkinson’s disease might help reduce breathing issues common in patients with Rett syndrome. The drug, sarizotan, may help reduce the frequency of breath holding, a potentially significant effect of Rett syndrome.

“We often see Rett patients holding their breath for long periods of time, up to 30 seconds at a time, behavior that can go on for hours,” said Alan Percy, M.D., professor of neurology in the Department of Pediatrics, medical director of the UAB Civitan International Research Center and a leading Rett syndrome expert. “Patients often end up swallowing large amounts of air, which can have a very detrimental effect on nutrition, a major issue for Rett patients.”

The study, to be held in four sites in the United States and several international locations, is looking to enroll patients with Rett syndrome who are 13 years and older, have a body weight of at least 55 pounds and experience multiple episodes of breath holding while awake during the day.

Percy says UAB is looking to enroll 10-15 patients locally. Participants will be followed for one year.

“Breath holding can be quite disruptive in younger Rett patients, although it usually subsides in early adulthood,” Percy said. “We currently do not have an effective medication that addresses breath holding. This is the first multisite trial of a potential therapy.”

While its mechanism of action remains unclear, Percy says sarizotan may help prevent breath holding by activating serotonin 1a receptors in the brain stem.

“While this is certainly not curative for Rett syndrome, it could be disease modifying,” Percy said. “This has the potential to be an important drug, as breath holding can be very disruptive and distressing to the family.”

The National Institutes of Health defines Rett syndrome as a neurodevelopmental disorder that affects girls almost exclusively. It is characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability.

The study is sponsored by Newron Pharmaceuticals U.S., Inc. Other study sites in the United States are the Altman Clinical and Translation Research Institute, University of California San Diego; Rush Medical University Center, Chicago; and Texas Children’s Hospital, Houston.
UAB’s Parpura invited to join Dana Alliance for Brain Initiatives
by Bob Shepard - December 09, 2016 

Vlad 1
UAB neurobiology professor Vladimir Parpura becomes the second UAB faculty with membership in the Dana Alliance for Brain  Initiatives.

Vladimir Parpura, M.D., Ph.D., a professor in the Department of Neurobiology (http://www.uab.edu/medicine/neurobiology/) in the School of Medicine(http://www.uab.edu/medicine/home/) at the University of Alabama at Birmingham  (http://www.uab.edu/home/), has been invited to become a member of the Dana Alliance for  Brain Initiatives (http://www.dana.org/About/DABI/). The Dana Alliance is a nonprofit organization  whose mission is to advance public education about the progress and benefits of brain research  and to disseminate information on the brain in an understandable and accessible fashion.   Parpura will be only the second member of the UAB faculty with membership in the Dana  Alliance, joining James MeadorWoodruff,  M.D., chair of the Department of Psychiatry. There are more than 550 neuroscientists worldwide in  the organization.

Outreach efforts of the Dana Alliance include organizing public forums such as an aging series targeted to older adults, facilitating speaking engagements, and supplementing K12 neuroscience curricula with publications and teaching materials through free, downloadable materials on the alliance website.  The alliance’s flagship event is the annual Brain Awareness Week Campaign, now in its 22nd  year. The upcoming campaign is March 1319,  2017.

Parpura earned his medical degree from the University of Zagreb in Croatia in 1989, and a  doctorate in neuroscience and zoology from Iowa State University in 1993. He was elected as a Member of Academia Europaea in 2012, and has held faculty appointments at Iowa State University, the University of California, Riverside, and the University of Rijeka, Croatia, before joining UAB.

Four new NSF grants — three in neuroscience — deepen UAB’s research portfolio, forge collaborations by Jeff Hansen

Alabama now has more EPSCoR Track II grants than any other state following the award of basic science grants meant to stimulate competitive research in regions of the country traditionally less able to compete for such research funds.

Four teams of University of Alabama at Birmingham researchers have been awarded National Science Foundation grants totaling $5.4 million meant to stimulate competitive research in regions of the country that are less able to compete for these research funds.

One research team supported by an NSF grant is in the College of Arts and Sciences’ Department of Chemistry, led by a polymer chemist who applies nanotechnology to biological and biomedical challenges. The three other grants will support basic neuroscience studies, one of UAB’s hallmark research strengths.

Lori McMahon, Ph.D., the Jarman F. Lowder Professor of Neuroscience, dean of the UAB Graduate School and director of the UAB Comprehensive Neuroscience Center, highlighted the three neuroscience EPSCoR grants at this fall’s Comprehensive Neuroscience Center retreat, calling them prestigious and competitive.

“UAB neuroscience has never had one NSF grant, and now we have three,” she said. “With the results of these grants, we can increase our funding beyond the National Institutes of Health.”

These four UAB grants, and one additional Alabama-related EPSCoR that supports research teams at the University of Alabama, Tuscaloosa, and the University of Mississippi, set a record, says Christopher Lawson, Ph.D., executive director of the Alabama EPSCoR program and a professor in the UAB Department of Physics.

“The state of Alabama now has more of the EPSCoR Track II grants than any other state; no state has ever had five.” 

Only 25 states, two territories and one commonwealth — areas that receive much less NSF funding than the major research universities in the other 25 states — qualify to compete for the Experimental Program to Stimulate Competitive Research grants, known as EPSCoR. The EPSCoR Track II grants are meant to level the playing fields among have and have-not research states, and applicants must form collaborations with researchers from other EPSCoR states. This means the UAB teams have formed synergistic partnerships and collaborations across the Birmingham campus and with scientists in other states to foster regional research strength. escor graphic

UAB neuroscience teams and their goals

The three neuroscience EPSCoR grants support a study to understand the initiation of epileptic brain seizures; a project to develop a new tool for optogenetics, which is the control of neural cells using light; and an effort to discover a universal rule for the relation between neural activity and increased blood flow in areas of the brain. In all three EPSCoR grants, UAB is a partner institution, and the lead institution is in another EPSCoR state.

“Several institutions reached out to UAB because we are so strong in neuroscience,” McMahon said. “There is a lot of UAB synergy around the three neuroscience EPSCoRs.”

McMahon says all three UAB neuroscience teams will meet regularly to share results and ideas.

Epileptic brain seizures

nsf grants martinFrom left: Roy Martin, Jerzy P. Szaflarski and Timothy Gawne.The current approach for epilepsy surgery at UAB involves two surgeries. The first implants electrodes into a patient’s brain for a two-week period to map the location of the seizure onset zone in the brain. The second operation cuts out the onset zone.

“Our goal is to one day not need invasive monitoring,” said Sandipan Pati, M.D., assistant professor of neurology. “That would mean one surgery instead of two, and the patient would not have to stay in the hospital for two weeks.”

The UAB team in the epileptic brain seizure study — headed by Jerzy P. Szaflarski, M.D., Ph.D., professor of neurology — is developing and validating software for noninvasive brain mapping that will allow caregivers to locate that part of the brain that initiates seizures and locate those parts that function in memory.

“We will provide a road map for the surgeons — where to operate to remove the thumb-sized part of the brain that kicks off seizures, and what parts of the brain to avoid,” Pati said, “so that patients will have no added memory deficits after the operation.”

The investigators will use magnetoencephalography, or MEG, to map electrical activity using the magnetic fields produced by natural electrical currents produced by the brain. The magnetic forces are measured from the outside of the brain as the top of a patient’s head fits into the MEG device, which looks something like a beauty-shop hair drier on steroids. Pati says the UAB team has preliminary data about using the MEG to identify the onset zone by its hyper-excitation, without the need to wait for seizures.

Other UAB investigators in the study are Roy Martin, Ph.D., associate professor of neurology, and Timothy Gawne, Ph.D., associate professor of vision sciences. The lead institution for the study is Louisiana Tech University, and the University of Arkansas is also a partner in the study.

New tool for optogenetics

nsf grants mcmahonFrom left: Mark Bolding, Lynn Dobrunz, Lori McMahon and Gary Gray.Optogenetics uses light to control cells in living tissue, after light-sensitive ion channels are introduced into the cells by gene manipulation. Then light is sent into the brain on a fiber-optic cable inserted into the brain, to make neurons fire or to stop neurons from firing. This control helps researchers learn how the brain is wired and how it works.

The optogenetics project will create technology to control the light-sensitive ion channels using low-power X-rays, thus allowing control of neurons from outside the body.

McMahon is the UAB co-principal investigator in this project, which is led by Clemson University. Other partner institutions are the University of New Mexico and the University of South Carolina. The Clemson researchers will develop special nanoparticles that emit light in response to X-rays, the New Mexico researchers will genetically modify the light-sensitive ion channels so that they can bind the nanoparticles, and the UAB researchers will test how those nanoparticles disperse in the brain and how these particles, when activated by X-rays, can turn on and off brain circuits.

“We are about to do the first validation,” McMahon said. “The entire four years of the grant is developing the tool. Then we can use it in animal disease models for Alzheimer’s disease, Parkinson’s disease and anxiety. The goal is to understand brain circuitry using preclinical models of neurologic disease and models of neuropsychiatric illness.”

Other UAB investigators are Lynn Dobrunz, Ph.D., associate professor of neurobiology; Mark Bolding, Ph.D., assistant professor in the Division of Advanced Medical Imaging Research, Department of Radiology, and director of the Civitan International Neuroimaging Facility; Kazutoshi Nakazawa, M.D., Ph.D., associate professor of psychiatry and behavioral neurobiology; and Gary Gray, Ph.D., professor of chemistry.

Neural activity and blood flow

nsf grants lubinJacques Wadiche, Farah Lubin and Paul Gamlin.It has long been known that neural activity is associated with increased blood flow, as the neurons need more oxygen and nutrients. In imaging with functional magnetic resonance, or fMRI, increased blood flow can be seen in parts of the brain as the subjects perform a task. But the resolution — both spatially and in time — is not sharp, and fMRI remains an indirect measure of neural activity.

The UAB team will use a very expensive infrared laser and microscope to peer beneath the surface of living brains to look at individual neurons and capillary beds.

“We will image cells in the brain using two-photon imaging,” said Paul Gamlin, Ph.D., professor of ophthalmology and UAB’s co-principal investigator in the neural activity and blood flow effort. “While monitoring neural activity, we will also monitor what the capillary bed is doing.”

“The question is, if we stimulate the cells, how precise is the blood flow change?”

Capillaries are the smallest blood vessels, bringing oxygen and nutrients to cells and taking away carbon dioxide and waste products. Networks of capillaries form tiny beds of vessels, and each capillary has a precapillary sphincter, a ring of muscle that can control blood flow, akin to crimping a garden hose to lessen water flow. It has been estimated that the human brain has 400 miles of capillaries, and that nearly every neuron in the brain has its own capillary.

Gamlin and others on the UAB team — Lawrence Sincich, Ph.D., assistant professor of vision sciences; Farah Lubin, Ph.D., associate professor of neurobiology; Jacques Wadiche, Ph.D., associate professor of neurobiology; and Yuhua Zhang, Ph.D., assistant professor of ophthalmology — can stimulate neurons nonphysiologically and see how the capillaries change. They will also look at physiological stimulation by shining light on one, two or three retinal cells in the eye and watching how neurons and capillaries in the visual cortex of the brain respond.

The lead institution in this project is the Medical University of South Carolina, and Furman University and the University of South Carolina, Beaufort, are partners in the study.

Detecting pollutants in Gulf Coast marine ecosystems

eugenia kharlampieva 2016Eugenia KharlampievaThe Gulf Coast aquatic ecosystem hosts important fishing grounds and aquaculture, which co-exist with trading ports, off-shore oil wells and production industries. The fourth UAB EPSCoR is aimed at monitoring the water quality of this ecosystem, under the lead of the University of Southern Mississippi.

Ten researchers at six institutions in Alabama and Mississippi will develop advanced polymer-based, selective sensing technologies to detect and analyze pollutants.

The UAB investigator is Eugenia Kharlampieva, Ph.D., associate professor of polymer chemistry. She will design and synthesize three-dimensional porous hydrogel microparticles. These particles will be filled with sensing molecules created by Marco Bonizzoni, assistant professor of chemistry at the University of Alabama, Tuscaloosa. These hydrogels will eventually become devices that can sense polycyclic aromatic hydrocarbons in sea water.

“Sea water is a challenge because it is very rich in ions from all that salt,” Kharlampieva said. “It is hard to find the right technology that will work in that environment.”

Other researchers in the grant are developing sensitive and selective sensors to measure levels of carbon dioxide, nitrates and phosphates. The goal is new classes of seawater quality sensors that are faster, simpler and less costly. Other partner institutions in the grant are the University of Mississippi, Mississippi State University and Jackson State University.
Molecular scissors could point the way to genetic cures

By Erin Burns, Amber Guidry, Nicholas Potochick, and Charles Buchanan • Photos by Steve Wood

Guan-En Graham is determined to find out exactly what happened to her father. When she was a child, he developed brain cancer. Since then, she has worked to understand the intricate genetic mechanisms that trigger brain diseases so that one day, perhaps, she can shut them down for good.

Now Graham might have the tool to do it. In the lab of Jeremy Day, Ph.D., the sophomore neuroscience major from Las Vegas is part of a UAB research team investigating CRISPR, a piece of gene-editing technology that could have the potential to prevent disease before patients start to suffer.

Precise and Programmable

CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, is essentially a pair of molecule-sized programmable scissors—scissors that work on the DNA inside living cells. In the few years since scientists have refined the technology, CRISPR has revolutionized gene editing.

Photo of Guan-En Graham, Jeremy Day, and Jasmin Revanna in Day's labJeremy Day (center) and undergraduate students Guan-En Graham (left) and Jasmin Revanna (right) use CRISPR technology to illuminate the power and reach of epigenetic modifications in brain diseases.

The concept of adding, deleting, or otherwise altering an existing DNA sequence is nothing new; scientists have done it in laboratories for decades. But earlier gene-editing technologies can produce “off-target” effects, unintentionally tinkering with other pieces of DNA. CRISPR is more precise, efficient, versatile, and affordable than its predecessors, which has changed how scientists address questions and the speed in which they answer them.

Day, a UAB School of Medicine assistant professor of neurobiology, studies epigenetics, a group of molecular modifications that influence gene activity without changing the DNA sequence. CRISPR enables his research group “to explore how epigenetic modifications affect expression of specific genes. The ability to express genes in a selective fashion gives rise to the amazing diversity of cell types that we possess.”

Jasmin Revanna, another neuroscience major working with Day, describes the work as “changing ‘tags’ on DNA that affect its function in the cell.” The goal is to discover the roles those tags, or epigenetic modifications, play in diseases that don’t result from DNA mutations, adds the freshman from Jacksonville, Alabama.

“We are applying this to addiction-related diseases to understand how drugs of abuse engage the epigenome to generate long-term alterations in neuron function and behavior,” Day says. The findings could lay the groundwork for a variety of CRISPR-related epigenetic treatments—perhaps boosting or restoring memories for Alzheimer’s patients or tamping them down for people with post-traumatic stress disorder. “While our current studies are in their infancy, this technology is a huge leap forward,” Day says.

Infographic showing the steps involved in CRISPR

Cut, Paste, Treat

CRISPR originated in certain bacteria, where it functions as protection against invading viruses. Essentially, it’s a “highly efficient and specific” cellular immune system, explains Tim Townes, Ph.D., professor of biochemistry and molecular genetics in the UAB School of Medicine. The molecular mechanism recognizes viral DNA and cuts it up to prevent the virus from replicating inside the bacteria.

Where CRISPR cuts DNA, researchers can delete or insert a DNA sequence. Townes’s lab has applied this technology to successfully correct the genetic mutation causing sickle cell disease (SCD), which can cause chronic pain and organ damage. Current SCD treatments are lifelong and can have severe side effects.

“All patients with SCD have the exact same mutation in the exact same location on the exact same gene—meaning we need to correct only one mutation in the bone marrow cells to cure someone of this condition forever,” Townes says. The process involves retrieving bone marrow cells from the patient, treating the genes, and then implanting the cells back into the patient. Because the cells are the patient’s own, there would be no need for a transplant or risk of rejection. “With CRISPR we have an effective rate of correction for the sickle cell mutation between 30 and 50 percent. Just that portion of cells is enough to cure someone of sickle cell,” Townes says.

Currently, each baby born in the United States is tested for the sickle mutation, allowing researchers to know within a month whether the baby will develop the disease. SCD symptoms typically do not appear until children are a year old, “which leaves 11 months to cure them, and they may never have to experience the disease,” Townes says. A similar approach could benefit patients with other diseases. In published research, Townes and his team have shown how they used CRISPR to correct the DNA that triggers severe combined immunodeficiency disease, in which children are born with no immune response.

A Key to Personalized Medicine

Both Townes and Day expect human clinical trials of CRISPR-based therapeutics to begin in the next few years. Genetic disorders arising from single-gene mutations, like SCD, are ideal CRISPR candidates because they require only one small correction to be made, and the correction is always the same. However, most genetic disorders aren’t so simple, involving complex mutations in multiple genes. As CRISPR technology improves, it may be adaptable for a wider range of disorders, and both Townes and Day predict that it will play a key role in the development of personalized medicine, with treatments tailored to each patient’s genetic makeup.

Photo of Tim TownesResearchers led by Tim Townes (left) have used CRISPR (illustrated above) to correct the genetic mutation causing sickle cell disease—a discovery that points to a potential cure.

Babies born in Alabama hospitals currently are tested for 35 diseases, “but for about the same price, we could sequence their genome” and pinpoint genes that put them at risk for disease, Townes says. Then, “long before someone develops one of these genetic predispositions, we could correct the gene so that they never experience that disease,” Townes says.

Even when gene editing is difficult or impossible, CRISPR’s ability to introduce desirable epigenetic modifications may become highly useful, Day adds. "This will be possible in several years as we develop our basic understanding of how epigenetic marks regulate single genes."

Safety Monitors

Could CRISPR lead science down a slippery slope, with people wanting to alter their genes—or their children’s genes—for cosmetic reasons, for example? Safety and ethical considerations are key to CRISPR’s progress, Day and Townes say. “We already use many different therapeutics that are capable of altering how our genes are expressed and capable of producing long-term effects,” Day says. “The ethical considerations that arise have more to do with the application of technology than with the technology itself. Ultimately, the benefits of CRISPR will outweigh potential risks, provided there is adequate screening and careful observation.”

Townes agrees, noting that “overall the scientific community has done well in regulating these new technologies and not acting irresponsibly.”

The Food and Drug Administration, which must approve any clinical trial of CRISPR in humans, also is developing regulations on safety and the use of gene-editing technology.

• Learn more about the groundbreaking research and educational opportunities in the UAB Department of Neurobiology and Department of Biochemistry and Molecular Genetics.

• Give something and change everything for School of Medicine researchers seeking cures for diseases and the patients who could benefit from them.

Published October 2016








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Congratulations to the following for their outstanding abstracts and poster presentations at the McKnight Poster Session held on Sunday, November 13, 2016 in San Diego, California.  It was very competitive this year, with a record 67 poster presenters from the various McKnight Institutes.  

First place winner was Joseph McQuail from the University of Florida, for his presentation of “Stress reactivity predicts impaired working memory in aging: vulnerability of GABAergic synapses.”

Representing the University of Arizona, Rachel Samson was awarded second place with “Expectation of large reward elicits bursts of beta-band oscillations in the aged rat amygdala.”

Third place
winner was Natalie Khoury from the University of Miami, for presenting “Elucidating the molecular mechanism behind the long-term cerebral ischemic tolerance mediated by resveratrol preconditioning.”


Join us in congratulating the winners for their outstanding work!