Improving lives of patients with neurological and psychiatric diseases

Neurological and psychiatric diseases affect 1 in 3 Americans with an estimated cost of $500 billion a year. New treatment opportunities are on the horizon as the neurosciences undergo a period of exponential growth. The field encompasses many disciplines, from molecular biology and psychiatry to radiology and pathology, making it extraordinarily challenging to develop highly interactive, multidisciplinary efforts translating basic science into effective clinical therapies.

Efforts must transcend disciplines, requiring cooperation of numerous scientists in multiple departments and labs, explains Ray L. Watts, MD, John N. Whitaker Professor, chair of UAB’s Department of Neurology, and director of clinical research in the Parkinson’s Disease and Movement Disorder Research Program.

“The increasingly sophisticated ability to regulate gene expression levels across cellular and temporal domains and monitor gene expression in living animals and brain-slice preparations offers an unprecedented opportunity to advance our understanding of neurological and psychiatric disorders,” says Kevin A. Roth, MD, PhD, director of UAB’s Division of Neuropathology.

Roth heads UAB’s new Comprehensive Neuroscience Center (CNC), which was created to meet these challenges and build on momentum brought by biomedical breakthroughs. One of the first of its kind in the United States, this center lays the foundation for an outstanding program in interdisciplinary neuroscience research and clinical care.

Modeled after UAB’s flagship Comprehensive Cancer Center, the CNC provides shared lab space, core facilities, and objectives for multiple departments and schools, including medicine, dentistry, engineering, public health, and others. The CNC’s current research strategy divides investigative efforts into 6 areas of concentration reflecting directions in neuroscience discovery: neurodevelopment and neurogenetics; neurodegeneration and experimental therapeutics; neuroregeneration and plasticity; behavioral and cognitive health; glial biology; and neuroimaging.

“The CNC removes roadblocks to collaboration, allowing us to build cross-campus initiatives that rapidly apply basic science discoveries to human neuroscience and neurologic and psychiatric diseases,” Watts says. “Applying basic research discoveries across disciplines will help reach our ultimate goal — creating new drugs and therapeutic strategies that improve the lives of patients with a spectrum of neurological and psychiatric conditions.”

Blueprint Center Core Facility

Recognizing the challenge faced by 21st century neuroscience, the National Institutes of Health (NIH) in 2004 designed the Neuroscience Blueprint — a formal partnership among 15 NIH institutes and centers that supports collaborative initiatives to develop research tools and infrastructure, takes advantage of economies of scale, and pools resources and expertise. “The days of pigeonholing neurologic and psychiatric diseases into subdisciplines of neuroscience are over,” says Roth, whose expertise lies in neuropathology and design of pharmacological strategies for altering neuronal cell death. Using mice with targeted gene disruptions, he investigates the role of molecules associated with cell death in nervous system development, brain tumor formation, and neurodegenerative diseases.

In 2005, the NIH’s Blueprint for Neuroscience Research awarded UAB one of its highly competitive grants, providing $8.6 million over 5 years to establish the Alabama Neuroscience Blueprint Center Core Facility, a regional hub emphasizing interdisciplinary work among UAB scientists and investigators from other NIH Blueprint centers. “This represents a truly collaborative effort, crossing institutional lines and synergizing activities of various disciplines,” Roth says.

Through 5 shared research cores, UAB scientists are working with NIH Blueprint-funded investigators from 6 regional institutions. “The Blueprint facility complements preexisting research endeavors and provides exceptional capabilities for generating and characterizing genetically modified mice,” says Watts, who emphasizes most core facilities and equipment are not disease-specific but support research and promote cross-fertilization in many areas, including physical medicine and rehabilitation, pediatrics, ophthalmology, and neurosurgery.

Limited core services began in October 2006, concurrent with a Web site launch (www.alneurosciencecenter.uab.edu). Roth expects the center to be fully operational by spring 2007.

Five Research Cores

Molecular engineering: This core focuses on creating new and better mouse models to aid understanding of nervous system function and disease, with an emphasis on generating targeting cassettes for production of transgenic and knockout animals.

Cellular and molecular neuropathology: A second core facilitates histopathological and molecular characterization of genetically modified experimental animals and neuropathological analyses of the novel transgenic mice. Enabling these analyses are a sophisticated stereology/morphometric system that performs advanced image analysis routines and a laser microdissection facility for collection of nervous system cell information.

Neuroimaging: Advanced fiberoptics and sensitive in vivo fluorescence imaging are modalities that enhance visualization of neuronal structure and function in living animals. Imaging technologies include single photon emission computed tomography, ultrasound, bioluminescence, and magnetic resonance imaging and spectroscopy (MRI/MRS).

Physiology and phenotyping: Investigators quantify in vivo physiology and phenotype metabolism and body composition in transgenic mice to characterize aspects of homeostatic physiology.

Cellular and synaptic physiology: Researchers employ intracellular and extracellular recording in brain-slice preparations. Using high-throughput data, investigators can characterize synaptic function and cellular physiology in the brains of animal models to determine if basic attributes of transmission and plasticity are intact. This core will assess synaptic function and cellular physiology in the hippocampus, cerebral cortex, and cerebellum; baseline synaptic transmission; and N-methyl-D-aspartate receptor function, among other measures.

UAB’s commitment to collaborative neuroscience research won the highly sought Blueprint grant, and initial steps include capitalizing on existing facilities, augmenting current research programs, and adding new equipment and faculty. Watts expects neuroscience faculty in various UAB departments to grow by 40 to 50 scientists in the next 5 years.

UAB’s departments and divisions with ties to neuroscience already boast some of the most dynamic leaders in their fields. Several eminent investigators have recently joined the university, bringing exceptional expertise to key areas of neurologic and psychiatric research and clinical care.

Center for Neurodegeneration and Experimental Therapeutics

Internationally known neurologist and John T. and Juanelle D. Strain Professor of Neurology David G. Standaert, MD, PhD, who joined UAB from Harvard University, directs the Division of Movement Disorders and the new Center for Neurodegeneration and Experimental Therapeutics. The interface between UAB’s active clinical enterprise and exceptionally strong basic science programs played a major role in Standaert’s decision to move to Birmingham.

“Our programs in neurodegenerative conditions, including Parkinson’s, Alzheimer’s, Huntington’s, amyotrophic lateral sclerosis, and others, are built on a strategy of rapidly translating discovery from genetics to mouse models to human research, and ultimately, to complete clinical application,” he says. UAB’s university-wide commitment to neuroscience is producing valuable synergy, helping basic scientists better understand the pressing clinical needs of patients with neurological and psychiatric diseases, he says.

“Scientists probably will work for generations before a comprehensive picture of the brain emerges,” Standaert says. “Interacting with clinicians can help scientists better appreciate which questions, if answered today, would make a real difference to patient care. Clinicians, who best understand their patients’ needs and the limitations of current diagnostic and treatment options, can provide critical perspective to individuals working in the lab.”

Standaert sees patients with Parkinson’s disease (PD) and other movement disorders and also has a clinical interest in dystonia, which can present diagnostic challenges. “Dystonia is not as well understood as Parkinson’s,” he says. “Recent research suggests excessive plasticity in the brain — an over-learning response that comes from intense training — may drive use-dependent dystonia, such as that experienced by musicians.”

Parkinson’s Disease
Watts, who joined UAB in 2003, has made PD and other movement disorders research priorities, creating the Parkinson’s Disease and Movement Disorder Research Program. His research shepherds discoveries of molecules that block or interfere with degenerative processes to clinical trials.

Current therapeutic PD trials are testing drugs such as rasagiline and carbidopa/levodopa/entacapone, which may improve motor function and quality of life. Researchers also are investigating possible hereditary components of PD and looking for disease markers in unaffected family members of Parkinsonian patients, Watts says. A study involving dopamine-producing retinal cell transplant therapy also is underway.

The American Parkinson’s Disease Association recently named UAB 1 of 8 Advanced Centers for Parkinson’s Research, a designation that supports basic and clinical PD investigations.

Patients in the PD and movement disorders clinics have access to clinical trials — more than 12 such studies are ongoing — as well as the latest medical and surgical options. As part of the PD treatment program, UAB neurosurgeon Barton L. Guthrie, MD, offers advanced surgical procedures, including deep brain stimulation, for select patients whose medications are no longer effective.

Learning and Memory
Department of Neurobiology Chair J. David Sweatt, PhD, is a globally recognized scientist who focuses on biochemical mechanisms underlying learning and memory. He directs the Evelyn F. McKnight Brain Institute, which recently received a $5 million grant to study age-related memory loss, and holds the Evelyn F. McKnight Endowed Chair for Memory and Aging.

Sweatt and colleagues are formulating and testing strategies to influence biochemical processes that lead to memory formation. “Increased understanding of signal transduction, or cellular signalling, among protein kinases in the hippocampus offer new targets for novel memory-loss medications. These drugs could potentially enhance memory by extending the activity of key proteins.”

Sweatt is investigating the roles of these hippocampal pathways in mouse models of epilepsy and Alzheimer’s disease. “We plan to capitalize on our recent insights into signal transduction mechanisms operating in hippocampal synaptic plasticity by combining in vitro biochemistry, electrophysiology, immunohistochemistry, and behavioral assays. Using both pharmacologic and genetic manipulations, we can investigate the molecular basis of normal learning and the biochemical derangements underlying pathological conditions affecting learning and memory,” Sweatt says.

Psychiatry

Heman E. Drummond Professor of Psychiatry James H. Meador-Woodruff, MD, who chairs the Department of Psychiatry and Behavioral Neurobiology, joined UAB in 2006 from University of Michigan’s renowned Molecular and Behavioral Neuroscience Institute.

Meador-Woodruff is known for his research in the neurochemical circuitry and gene expression of schizophrenia. His lab’s primary focus is studying limbic circuitry neurochemistry and neuroanatomy underlying the pathophysiology of major psychiatric disorders, especially schizophrenia. Researchers are investigating how different parts of the brain communicate with each other via chemical signals, and how this communication is disrupted in schizophrenia. “We are interested in elucidating circuit-specific patterns of expression and regulation of key neurotransmitter systems in the brain, particularly the glutamate and dopamine systems,” he says.

Since his arrival at UAB, Meador-Woodruff has been building an in-depth research program in schizophrenia, capitalizing on already strong clinical programs in the department. He has recruited 7 new faculty who focus exclusively on schizophrenia research. One of these new scientists, Adrienne C. Lahti, MD, was recruited to direct the Neuroimaging and Translational Research Laboratory, a neuroimaging program using functional MRI and position emission tomography in individuals with schizophrenia who show abnormal brain activity patterns during studies with the noninvasive technology. She also directs the new Schizophrenia Program.

Rosalinda C. Roberts, PhD, who brings several large grants to UAB, is examining postmortem ultrastructural abnormalities in the brain tissue of individuals with schizophrenia and also is establishing a statewide repository of brain tissue from people with major psychiatric conditions.

“During the next 6 months, our goal for the Schizophrenia Program is conducting sophisticated lab-based studies that we can rapidly move into cutting-edge treatments,” Meador-Woodruff says.
“This year, we also plan to recruit a number of new faculty who will establish a similar research program focused on mood disorders, which are major psychiatric illnesses affecting 1 in 4 people at some point in their lives.”

Center for Glial Biology
Neurobiologist Harald W. Sontheimer, PhD, who directs UAB’s Civitan International Research Center and the new Center for Glial Biology in Medicine, has studied glial cells for 20 years. Glial dysfunction is critically important in many devastating neurological disorders, including glial-derived brain tumors, multiple sclerosis, brain and spinal cord injury, developmental disabilities, and epilepsy. This groundbreaking center provides exceptional resources and research infrastructure and connects the labs of more than 29 UAB principal investigators working on glial biology.

Sontheimer’s recent research suggests sulfasalazine is a promising deterrent to glioblastoma multiforme, one of the most deadly human cancers. Further work targets cell-volume changes and the role of ion channels during glioma cell migration, amino acid transporters’ effects on growth and invasion of primary brain tumors, and the role of calcium-activated potassium channels in malignant glioma growth. Sontheimer also discovered chlorotoxin, a scorpion-derived peptide that can be used as an anti-invasive agent in gliomas. Investigators have successfully studied a synthetic version of this peptide, called TM-601, for malignant glioma in a recently concluded phase 1 clinical trial. A national phase 2 study is open for patient enrollment.

World-class Neuroscience
As part of its commitment to innovative neurological and psychiatric research, UAB has dedicated significant space to the neurosciences. The new Richard C. and Annette N. Shelby Interdisciplinary Biomedical Research Building has 3 floors devoted to interdisciplinary neuroscience programs. Neurology, neuropathology, and neurobiology labs are based in the Shelby building, organized along programmatic themes.

Disease-oriented neuroscience research labs, including those of Standaert, Meador-Woodruff, and Sontheimer, are in the Civitan International Research Center. Located in close proximity are labs operated by faculty studying spinal cord injury and paralysis, childhood brain injury, schizophrenia and depression, and developmental disorders such as autism. “These programs also will benefit from Blueprint core resources and an interactive, collaborative atmosphere that promotes cross-fertilization of ideas,” Roth says.

With such outstanding research and discovery, UAB is entering a new phase as a world-class neuroscience research facility. “The CNC is the epicenter for neuroscience research, facilitating the efforts of our existing centers,” Roth says. “We have embraced the NIH Road Map philosophy that the best way to affect patient care is recruiting people from different fields to apply basic research discoveries across disciplines. It is the way medicine should be done.”

“Diseases of the nervous system are among the most physically and emotionally devastating illnesses and often rob patients of hope, dignity, and potential,” Watts says. “The cutting-edge treatments we are working on today have potential to change clinical practice in the next 5 to 10 years. Our critical mass of investigators, who are experts in their fields and strongly committed to collaboration, will lead us into the future.”

For more information
Dr. Ray Watts
Dr. James Meador-Woodruff
Dr. Kevin Roth
Dr. Harald Sontheimer
Dr. David Standaert
Dr. David Sweatt
1.800.UAB.MIST
mist@uabmc.edu