• Brain Imaging Research
• Brain Tumors
• Cerebrovascular Diseases
• Cerebrovascular Diseases & Aging
• Neuronal Ischemia Cell Death
• Cortical Mapping
• Developmental Disorders
• Epilepsy
• Glial Neurology Laboratory
• Multiple Sclerosis & Neuroimmunology
• Neurocritical Care Research
• Neurodegenerative Diseases & Repair
• Alzheimer Disease
• Amyotrophic Lateral Sclerosis (ALS)
• Multiple Sclerosis
• Neural Plasticity & Neuro-Repair
• Parkinson Disease
• Prion Disease
• Peripheral Neuropathy
• Spinocerebellar Ataxia & Ion Channel Disorders
• Neurovirology
• Oligodendrocyte Biology & Myelin Studies



• Learn more about our Clinical Trials


• Return to the Main Research Page

• Dr. Small uses functional magnetic resonance imaging (fMRI) to study the organization of the normal human cerebral cortex and the changes that it undergoes after neurological injury, particularly stroke. Damage to the cerebral cortex has profound effects on such functions as learning, memory, language, and complex motor activity. Damage to structures that must communicate with the cortex or damage to the communication network also causes serious impairments. By studying the neuroanatomical substrates of recovery from injury, Dr. Small is attempting construct a functional basis for neurological rehabilitation that is grounded in basic neuroscience. Current projects in the Small group are in the areas of language and motor function, and are concerned with both the normal anatomy of these functions and their recovery after stroke. In the study of normal adults, the lab has found that the language areas of the brain are more widely distributed than previously thought, extending to brain regions that are anatomically removed from those originally postulated by Broca, Wernicke, and Déjérine, and extending to both cerebral hemispheres. Furthermore they have discovered that the parts of the brain that previously appeared specialized for language production (i.e., Broca’s area and ventral premotor cortex) play a fundamental role in language comprehension as well, by a process in which the listener uses this premotor language production system to make guesses about what he or she is hearing. In hand motor function, Dr. Small’s laboratory has found that left and right handed people use somewhat different brain networks when making simple and complex finger movements. Further, the brain seems to encode such finger movements by both individual muscle and pattered movement, expanding one view of motor representations of the cortex. Finally they have demonstrated a critical role for the cerebellum contralateral to the injury in mediating successful recovery from stroke.

• Richard Kraig MD PhD focusses his research on deciphering how the brain can protect itself against neurological disease. The brain is unique among organ structures. It can alter its regional, cellular and molecular structure in response to activity. This classically is evidenced by Hebbian synaptic plasticity but it also extends to environmental enrichment (i.e., increased intellectual, social, and physical activity), which protects the brain against neurodegeneration. The mechanisms by which naturally increased brain activity strengthens brain are largely unknown. Deciphering the bases by which increased brain from environmental enrichment alters both the form and function of brain has immense clinical value since environmental enrichment reduces subsequent neurological disease by half without negative sequelae.
  
  Dr. Kraig's work, and that of others, shows that learning involves increased production of tumor necrosis factor alpha (TNF-a), one a group of innate cytokines, typically recognized for their involvement as early responders to disease. Furthermore, his work shows that neuroprotection from activity depends on intrinsic production of TNF-a. This is an adaptive change that requires time to develop and extinguishes if not maintained by activity. Cytokines, including TNF-a, alter tissue structure and function by altering gene expression of related transcription factors, growth factors and anti-apoptotic genes.
  
  TNF-a and the other innate cytokines are highly pleiotropic and interactive. Accordingly, Dr. Kraig's lab has developed cell-specific genomic and proteomic techniques to acquire the “vocabulary” needed to understand the “syntax” of activity-dependent neuroprotection via the application of computational analysis strategies.
  
  Dr. Kraig uses in vitro and in vivo animal models of epilepsy, stroke, aging, and migraine as our exemplary diseases for study. They use cellular and molecular imaging strategies as well as genomic and proteomic techniques and computational analyses of data from these approaches to search for the “signaling syntax” by which natural neural activity makes brain more resilient to disease. Their tools include real-time cellular imaging, laser dissection microscopy, real-time RT-PCR, semi-quantitative cellular cytological and immunohistochemical imaging, all proteomic tools (including bead-based, multiplexed ELISAs), and nanoparticle gene delivery systems now in development.
  
  Specific Research Projects:
  
  
  1. The mechanisms and consequences of spreading depression
  2. The mechanisms by which brain activity results in neuroprotection
  3. How sleep modulates activity-dependent neuroprotection
  4. How cold generates neuroprotection
  5. Development and use of nanoparticle-based gene delivery for epilepsy treatment
  6. Development and use of macrophage-nanoparticle gene delivery systems for treatment of brain disease

• James Brorson MD is interested in how glutamate-mediated "excitotoxic" stress contributes to neuronal death in several neurodegenerative diseases and ischemic stroke. Dr. Brorson is attempting to understand the molecular basis for functional properties of glutamate receptors, particularly those of the AMPA receptor class, and relate the subunit expression patterns in specific neurons to their selective vulnerability to glutamate-mediated cell death. He employs both electrophysiological and molecular methods to relate functional properties of expressed glutamate receptors to expression patterns of subunits and vulnerability to excitotoxic death in neurons growing in primary dissociated cultures or in chronic organotypic slices. Recent studies have focused on modeling ischemia-reperfusion in neurons in a realistic way that includes features of excess glutamate as well as oxygen and substrate depletion during real-time fluorescence imaging of neurons in order to understand the timing and molecular mechanisms leading to neuronal death. Endogenous systems of transcription factors including Hypoxia-inducible factor-1 and signaling molecules such as nitric oxide may play both protective and destructive roles during reperfusion injury, depending on the levels and timing of their expression. Understanding the responses to injury may point to novel therapeutic targets for neuroprotection during the reperfusion phase of ischemic stroke.

• V. Leo Towle PhD has focussed his research to utilize functional MRI, direct electrophysiologic cortical recordings obtained during surgery, and noninvasive human cerebral evoked potentials as tools for understanding the functional organization of the human neocortex. A primary focus is to relate electrophysiologic findings to specific brain areas which can be imaged with MRI. The non-invasive electrophysiologic findings are compared to histology, intraoperative cortical mapping studies and parallel noninvasive functional MRI findings. Currently investigations involve the accuracy of dipole models, ECOG patterns, and the development and lateralization of language in epileptic and normal subjects using function MRI. This research has both practical value for neurosurgical procedures and theoretical implications for theories of brain organization and development. Dr. Towle has also studied cognitive event-related potentials as they relate to sensory and cognitive dysfunction in multiple sclerosis (MS), stroke and renal disease patients participating in drug trials.

• William Dobyns MD (Department of Human Genetics) research focus over the past two decades has centered on the genetic basis of human brain malformations, and bringing new discoveries back to clinical practice. Several different types of malformations, including agenesis of the corpus callosum, Dandy-Walker malformation, congenital microcephaly, lissencephaly, cobblestone malformation and polymicrogyria are typically associated with developmental abnormalities especially mental retardation, motor abnormalities (cerebral palsy) and epilepsy. Dr. Dobyns research uses human brain malformations as tools to map and clone important developmental genes, and brings these new discoveries back to patients and families by way of more accurate information regarding diagnosis, prognosis, clinical management and genetic counseling. In addition, as epilepsy affecting more than 80% of patients in most groups these conditions represent a paradigm for understanding the pathobiology of some forms of epilepsy.
  
  Dr. Dobyns research program has three components that span the translational spectrum:
  
  
  1. Patient-oriented research designed to identify and study patients with brain malformations;
  2. Disease-oriented research directed toward finding the molecular basis of a disorder; and
  3. Patient-oriented research, which applies our new knowledge to the care of patients and families.
  
  Identification of the genes involved in these malformations will help to define new molecular pathways and the location of these genes within each pathway. Close collaboration with mouse geneticists, including at the University of Chicago, will increase the power of gene discoveries by manipulating homologous genes in the murine system.



• Kathryn Millen PhD (Department of Human Genetics) is interested disorders of the cerebellum, the primary center of motor coordination in the central nervous system. Cerebellar disorders in both mouse and humans cause ataxia, tremor and abnormal eye movements. The cerebellum is also involved in cognitive processing deficits and sensory discrimination in multiple medical conditions including pervasive developmental disorders of childhood such as autism. Dr. Millen’s group is attempting to discover molecular and cellular mechanisms by which the cerebellum is formed in the mouse as a paradigm for human congenital cerebellar malformations and other developmental disorders. This is based on the hypothesis that similar patterning defects underlie mouse and human malformations. Several mouse mutants with severe cerebellar defects have been described and attributed to disrupted mechanisms of pattern formation during early embryogenesis. Currently, work focuses on several mutants, including the dreher mouse, in which the dorsal signaling center in the developing CNS, the roof plate, is missing in homozygous mutant mice. Neurons along the entire dorsal CNS, including the cerebellum, are inappropriately patterned and differentiate abnormally. Dr. Millen’s group has identified mutations in the Lmx1a gene as the cause of the dreher phenotype. Lmx1a now provides an entry point into the previously unknown molecular pathway of roof plate formation and function. Through use of gene expression arrays and chick electroporation technologies they are defining other genes in the Lmx1a roof plate cascade.
  
  Dr. Millen’s group has recently extended their analysis to congenital human cerebellar malformations particularly Dandy-Walker malformation (DWM) syndrome, a common, but poorly understood congenital cerebellar malformation. Recently, they demonstrated that heterozygous loss of two dorsally expressed genes, ZIC1 and ZIC4 is involved in DWM and have generated mouse models with Zic1+4 deletions. Sequence analysis of these genes in DWM patients suggests that ZIC4 mutations increase susceptibility to DWM alone, but are not sufficient to cause DWM. The likely oligogenic or polygenic model of inheritance has led to an active search for additional DWM loci and ZIC1/4 interacting genes using array comparative genomic hybridization. An understanding of the basis of this and other common brain malformations will not only provide valuable, currently unavailable diagnostic information but may also lead to treatments for those with the congenital malformation. By combining the power and strengths of both mouse and human genetics, the studies in Dr. Millen’s lab is providing clinically relevant data leading to better diagnosis and treatment of human congenital cerebellar malformations as well as lead to a more comprehensive understanding of the basic biology and genetics of cerebellar development.

• John Ebersole MD directs a research program aimed at:
  
  
  1. Clarifying the relationships between cerebral electrical activity and the resultant scalp EEG; and
  2. Developing and validating computational techniques of functional imaging and seizure localization using scalp, intracranial EEG, and magnetoencephalography (MEG).
  
  Over the past fifteen years research from his laboratory has established the usefulness of spike and seizure dipole modeling with both EEG and MEG in order to localize non-invasively epileptogenic foci in epilepsy surgery candidates. He is a foremost proponent of and authority on the use of source models in the evaluation of epilepsy. Ongoing projects include studies of the accuracy of dipole and other extended source models of epileptic foci using simultaneously recorded scalp and intracranial EEG, comparisons of real-time EEG imaging with other functional imaging techniques using three-dimensional co-registrations, and the development of a new spatio-temporal analysis technique for intracranial EEG utilizing field and source display on the patient’s reconstructed cortex. These direct applications of neurocomputational, neuroimaging, and electrical engineering developments to the evaluation of epileptic foci in the human brain are an example of translational research at its best.



• Maria Baldwin MD is interested in research involving characterization of various periodic lateralizing epileptiform discharges (PLEDS) patterns and treatment issues involving PLEDS plus patients.



• James Tao MD PhD is interested in determining the cerebral substrates of scalp EEG epileptiform patterns, in order to improve the accuracy of non-invasive seizure localization during epilepsy surgery. His long-term interests include investigations of the mechanisms of epileptogenesis and of new modalities of epilepsy therapy. Current projects include:
  
  
  1. The impact of cerebral source area and synchrony on recording scalp EEG ictal patterns; and
  2. The pathophysiology of interictal temporal delta activity (ITDA) and its value in localizing epileptogenic zone.
  
  His long term goals are to investigate the electrophysiological behavior of cerebral epileptogenic networks and the mechanism of epileptogenesis at the neural network level in order to identify new preventive and therapeutic modalities.



• Jan M. Ramirez PhD (Department of Organismal Biology and Anatomy) studies epileptogenesis using excised human tissue from epilepsy surgery to produce neocortical slices. This approach has been able to allow one to predict the optimal anti-epileptic drugs effective at stopping recurrent seizures in at least four patients after neurosurgery. Dr. Ramirez also studies rhythmic activity generated by the in vitro respiratory network of the mouse medulla to understand neuronal control of breathing using slice electrophysiological and immunohistochemical techniques. These studies have important basic scientific and clinical implications, such as understanding the underlying causes of sleep apnea, periodic breathing, erratic breathing in Rett Syndrome and sudden infant death syndrome (SIDS). Dr. Ramirez is also investigating bursting in dopaminergic neurons and exploring mechanisms that lead to cell death in dopaminergic neurons of the substantia nigra. Calcium influx could potentially explain the vulnerability of these neurons.



• Wim Van Drongelen PhD (Department of Pediatrics) has focussed his research on the long-range goal of optimizing therapeutic intervention in pediatric epilepsy by improved spatial and temporal localization of seizure activity and examining the underlying mechanisms in the pathogenesis of seizures. His research focuses on:
  
  
  1. Underlying neuronal mechanisms in epilepsy (synchrony, recruitment, oscillation, weak coupling);
  2. Relationships between neuronal activity at different scales (neuron, network, brain);
  3. Detection and prediction of brain electrical activity during seizures using various signal processing techniques (correlation dimension, Kolmogorov entropy, wavelet analysis);
  4. Localization of sources from surface recordings (dipole analysis, MUSIC, LORETA, spatial filtering); and
  5. Monitoring of the nervous system in the intensive care environment (EEG, evoked potential).

• Glial Neurobiology Laboratory - Betty Soliven MD is interested in CNS and peripheral nerve demyelinating diseases. One area of research concerns immune mechanisms that underlie peripheral nervous system demyelination. She is studying s line of the non-obese diabetic (NOD) mouse that was genetically engineered to be deficient in the major histocompatability complex gene product, B7.2. Dr. Soliven and colleagues found that these mice do not develop diabetes, but instead develop a progressive autoimmune polyneuropathy (SAP), with electrophysiologic and histologic features resembling chronic immune demyelinating polyneuropathy (CIDP). This model is unique in that, in the absence of B7.2, there is a shift from one autoimmune disease (type 1 diabetes) to another (SAP). Dr. Soliven’s group is using this model to investigate the link between islet cell and peripheral nervous system autoimmunity in order to characterize pertinent antigen/s that elicit T cell and possibly B cell reactivity, and to examine the effect of new drugs or therapeutic approaches for the treatment of inflammatory neuropathies.
  
  Dr. Soliven’s group is also interested in signal transduction mechanisms in oligodendrocytes and Schwann cells. They have studied the role of different potassium channel subtypes in oligodendroglial (OLG) regeneration and recovery from demyelination. Her group is also studying autocrine signaling of glial-derived neurotrophic factor in Schwann cells and the effect of sphingosine-1-phosphate (S1P) receptor modulators, and AT motif-binding factor 1 in cell cycle control in oligodendrocytes. Finally, Dr. Soliven directs a significant effort in training fellows to assist several investigators at The University of Chicago in the electrophysiological characterization of peripheral nervous system function in novel mouse mutants which are models for human neurological disease.

• Anthony Reder MD has focussed his research on the interaction between the central nervous system and the immune system; Dr. Reder is investigating expression of lymphocyte surface molecules necessary for immune activation, and also regulation of cytokine and interferon (IFN) genes after IFN-beta activation. Dr. Reder’s group has recently found an increase in the B7 costimulatory molecule on lymphocytes in active MS, which was corrected by IFN therapy as well as a specific defect in IFN signaling during active MS. His group also studies experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The lab has also studied regulation of killer T cell killing of astrocytes by using hormones and lymphokines to modify astrocyte glial surface antigens and secretion of cytokines.



• Barry G.W. Arnason MD focusses his reseach interests on understanding the interplay between the immune and nervous systems. Insights from both in vitro and in vivo models studied in his lab have contributed to our understanding of the disease mechanisms underlying T cell and B cell autoimmune syndromes of the nervous system as exemplified by multiple sclerosis (MS) and myasthenia gravis. The role of interferons, in particular the role of interferon-B, in moderating disease pathogenesis in MS has been an ongoing research effort of the group. Interferons are cytokines secreted by many cell types that possess immuno-modulatory activity. A second interest of the lab is examining the role of CD8+ suppressor T cells in modulating immune activation. Whereas activating Th1-type CD4+ T cells are widely recognized as a critical lymphocyte population for disease pathogenesis in MS, CD8+ suppressor T cells can down-regulate the activity of the Th1-type CD4+ T cell. Despite the critical role of T cells in MS pathogenesis, macrophages are the final vectors of tissue destruction in MS. Upon infiltrating the CNS, activated T cells secrete cytokines which in turn recruit activated macrophages resulting in tissue destruction. Recent efforts in the lab have focused on the development of immunomodulatory agents that have the potential to transform activated, pro-inflammatory macrophages to a more protective type.



• Brian Popko PhD has a long-standing interest in the effects that CNS inflammation, a key aspect of MS, has on oligodendrocytes and myelin. He has used in vitro and in vivo models to show that the inflammatory response has a direct deleterious effect on oligodendrocytes. The underlying hypothesis of his work is that myelinating oligodendrocytes, because of their need to synthesize enormous amounts of membrane lipids and proteins, are particularly sensitive to disruptions in the protein secretory pathway. Researchers in his lab have reported that the deleterious effects of the inflammatory response on developmental myelination and the remyelination of demyelinated lesions are associated with the activation of the ER stress pathway in oligodendrocytes. His goal, in understanding the ER stress pathway, is to enable the identification of therapeutics that may protect oligodendrocytes and their adult progenitors from the harsh CNS environment present in MS patients.

The Neurological Complications of Acute Liver Failure

Novel Approaches to In-Field Detection of Intracranial Mass Lesions

Brain Swelling from Large Hemispheric Infarctions

Novel Approaches to Establishing Regional Brain Hypothermia

Management of Patients with Intracerebral Hemorrhage

Neurological Prognostication, Brain Death and Neuroethics

Approach to Nourishment of Neurocritical Care Patients

• Sangram Sisodia PhD has focused his research on the cellular and molecular biology of the B-amyloid precursor protein (APP), or presenilins (PS1 and PS2), molecules that are mutated in autosomal dominant, familial forms of Alzheimer's disease (FAD) over the past 18 years. His work integrates genetic, neurobiologic, molecular and cellular methodologies. He has demonstrated that APP is subject to rapid anterograde transport and subject to proteolytic processing at, or near, terminal fields in the CNS. His ongoing investigations are aimed at examining regulation of APP trafficking and processing in vivo using cellular imaging and biochemical approaches that rely on introduction of recombinant lentiviral-driven APP-GFP chimeras into cultured neurons and hippocampal slices. In order to assess the function of PS, he has used gene targeting strategies; PS1-deficient animals die in late embryogenesis due to defective Notch signaling that is in large part, the result of failed intramembranous, “y-secretase” processing of a membrane-bound Notch substrate. Genetic and biochemical evidence has revealed that PS interacts with nicastrin, APH1 and PEN-2 in high molecular weight complexes, and Dr. Sisodia’s group is actively engaged in cell biological, biochemical and structural studies to understand the temporal assembly of these membrane proteins, the nature of subunit interactions and the enzymatic mechanism(s) by which the complex promotes "y-secretase" processing of Notch, APP and other type 1 membrane proteins.
  
  A significant effort of the Sisodia laboratory has been to develop and characterize transgenic animals that express FAD-linked variants of APP and PS1 and mice with conditionally inactivated PS to clarify the underlying biochemical and pathophysiological alterations that cause AD and issues relevant to axonal trafficking of membrane proteins, neurotransmission, neuronal vulnerability, neurogenesis, gene expression and APP/AB metabolism. More recently, they have demonstrated that enriched environments and exercise modulate A? metabolism and deposition in vivo, and are investigating a gene expression profile our ongoing efforts are focused on the role of polypeptides encoded by genes that are selectively regulated in these settings.



• Gopal Thinakaran PhD (Department of Neurobiology) focuses on the cell biology of AB production. He is particularly interested in defining regulation of APP trafficking and defining subcellular sites of APP processing by BACE1 and y-secretase. His group is also interested in y-secretase processing of proteins that play important functions in the nervous system such as Notch and DCC. He uses an integrated approach that combines hypothesis driven mutagenesis, biochemical characterization, and detailed subcellular localization and live imaging strategies to dissect the regulation of AB production and intramembranous cleavage of select type I membrane protein substrates of y-secretase. Similarly, initial promising pre-therapeutic trials of inhibition of y-secretase with highly selective inhibitors were found to cause adverse effects related to mechanism based toxicity, inhibition of Notch processing. Dr. Thinikaran’s research on metabolic pathways that regulate AB production is highly relevant to therapeutic targeting of APP secretases in a manner that selectively attenuates APP processing without adversely affecting Notch cleavage. Consequently, he believes that his studies will be critical to develop novel rational Alzheimer’s disease therapeutics aimed at reducing AB burden in the brain.

• Raymond Roos MD is interested is the delineation of genes and gene products critical to the death and survival of neurons, especially related to neurodegenerative diseases such as amyotrophic lateral sclerosis. One of the focuses of the research is the pathogenesis of familial ALS that results from mutation in superoxide dismutase type 1 (SOD1). The Roos lab makes use of mouse models that carry the mutant SOD1 gene as a transgene in order to clarify why motor neurons die. A theme that the lab is especially interested in is related to the role of misfolded proteins in ALS and other neurodegenerative diseases. An underlying hypothesis of these studies is that understanding why neural cells die as a result of mutant SOD1 (or particular virus infections) will clarify the pathogenesis of neural cell death in sporadic ALS, i.e., there is a final common pathway of neural cell death.



• Kamal Sharma PhD (Department of Neurobiology) is studying neurons that generate rhythmic behaviors that are thought to populate discreet regions of the nervous system. Ensembles of such neurons functioning together are called central pattern generators. His main goal is to test the function of molecularly defined interneurons and to map their function in relation to the respiratory and locomotor rhythm generators. The first key is identification of genes that are expressed in small subset of neurons in the spinal cord and brainstem. Dr. Sharma generates transgenic mice using homologous recombination in the ES cells, makes electrophysiological recordings of the motor output, and performs behavioral analysis of the motor function. He has used targeting vectors designed to achieve expression of axonal marker, tau-myc, selective ablation of the targeted neurons by the expression of Diptheria Toxin (DTA), selective silencing of the targeted neurons by the expression of inward-rectifying potassium channel, and regulated, inducible expression of the transgene using the tTA, TetO gene expression system. Interestingly Dr. Sharma successfully targeted excitatory interneurons that use glutamate to regulate the respiratory and the locomotor rhythm. Neurons that regulate the respiratory rhythm are located in the medullary reticular formation while those that regulate locomotion are located in the ventral laminae of the appropriate spinal segments. Recently, they successfully targeted hindbrain reticulospinal neurons, for which genetic ablation provides a mouse model for spinal cord injury. These transgenic mice are being evaluated for signs of autonomic dysreflexia, the most common cause of death following spinal cord injury.

• Anthony Reder MD has focussed his research on the interaction between the central nervous system and the immune system; Dr. Reder is investigating expression of lymphocyte surface molecules necessary for immune activation, and also regulation of cytokine and interferon (IFN) genes after IFN-beta activation. Dr. Reder’s group has recently found an increase in the B7 costimulatory molecule on lymphocytes in active MS, which was corrected by IFN therapy as well as a specific defect in IFN signaling during active MS. His group also studies experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The lab has also studied regulation of killer T cell killing of astrocytes by using hormones and lymphokines to modify astrocyte glial surface antigens and secretion of cytokines.



• Barry G.W. Arnason MD focusses his reseach interests on understanding the interplay between the immune and nervous systems. Insights from both in vitro and in vivo models studied in his lab have contributed to our understanding of the disease mechanisms underlying T cell and B cell autoimmune syndromes of the nervous system as exemplified by multiple sclerosis (MS) and myasthenia gravis. The role of interferons, in particular the role of interferon-B, in moderating disease pathogenesis in MS has been an ongoing research effort of the group. Interferons are cytokines secreted by many cell types that possess immuno-modulatory activity. A second interest of the lab is examining the role of CD8+ suppressor T cells in modulating immune activation. Whereas activating Th1-type CD4+ T cells are widely recognized as a critical lymphocyte population for disease pathogenesis in MS, CD8+ suppressor T cells can down-regulate the activity of the Th1-type CD4+ T cell. Despite the critical role of T cells in MS pathogenesis, macrophages are the final vectors of tissue destruction in MS. Upon infiltrating the CNS, activated T cells secrete cytokines which in turn recruit activated macrophages resulting in tissue destruction. Recent efforts in the lab have focused on the development of immunomodulatory agents that have the potential to transform activated, pro-inflammatory macrophages to a more protective type.



• Brian Popko PhD has a long-standing interest in the effects that CNS inflammation, a key aspect of MS, has on oligodendrocytes and myelin. He has used in vitro and in vivo models to show that the inflammatory response has a direct deleterious effect on oligodendrocytes. The underlying hypothesis of his work is that myelinating oligodendrocytes, because of their need to synthesize enormous amounts of membrane lipids and proteins, are particularly sensitive to disruptions in the protein secretory pathway. Researchers in his lab have reported that the deleterious effects of the inflammatory response on developmental myelination and the remyelination of demyelinated lesions are associated with the activation of the ER stress pathway in oligodendrocytes. His goal, in understanding the ER stress pathway, is to enable the identification of therapeutics that may protect oligodendrocytes and their adult progenitors from the harsh CNS environment present in MS patients.

• Nicholas Hatsopoulos PhD (Department of Organismal Biology and Anatomy) studies the neural basis of motor control and learning. He is investigating what features of motor behavior are encoded and how this information is represented in the collective activity of neuronal ensembles in the motor cortex. He is also interested in what way these representations change as motor learning occurs. Specifically, he is trying to understand how neuronal ensembles in the cortex act together to control, coordinate, and learn complex movements of the arm and hand. Dr. Hatsopoulos’ research studies, the electrical discharge of many motor cortical neurons is recorded using multi-electrode arrays while animals perform various motor behaviors with the goal of asking four fundamental questions:
  
  
  1. What motor features are encoded in motor cortical ensembles;
  2. How they are encoded in motor cortical ensembles;
  3. Whether these feature codes exhibit plasticity as a consequence of motor learning; and
  4. What is the nature of the transformations that occur between different motor cortical areas.
  
  Current results suggest that specific spatio-temporal patterns of activity across multiple neurons encode aspects of movement that are not revealed from single electrode recording.
  
  Beyond the basic scientific questions the applied goals of this research are to develop a brain-machine interface by which a monkey or human can control an external device in real-time by activating the appropriate neuronal signals. This research has lead to a FDA IDE clinical trial conducted by a company called Cyberkinetics Neurotechnology Systems, to determine whether patients with spinal cord injuries and ALS can use motor cortical signals to control a computer cursor. Implants have recently been made in two tetraplegic patients using this same array technolog, enabling recording of multiple signals from neurons in the motor cortex of these patients. It has been shown that they can voluntarily activate those neurons when imagining moving their paralyzed arms, and by feeding these signals through various decoding algorithms they can voluntarily guide the movement of a cursor in a goal-directed fashion.

• Richard Penn MD (Department of Surgery, Section of Neurosurgery) studies patients with movement disorders, such as Parkinsons disease in several interrelated investigations to improve treatment and understand underlying pathophysiology. Local field potentials and microelectrode recording done on patients having placement of deep brain stimulating electrodes are used to study tremor pathways. Other experiments have these patients make controlled movements in learning tasks and the single unit responses in the basal ganglia structures are recorded. The effects of deep brain stimulation on learning tasks after implantation will be studied and compared to intraoperative findings.


A second area of research focus is on drug distribution in the brain. Using model gels and animal experiments Dr. Penn’s group is investigating the distribution of medications directly infused into the brain tissue. Quantitative measurements are used to compare different infusion routines (diffusion and convection enhanced). The goal of this translation research is to improve drug delivery of an immunologically targeted drug against gliomas and neurotrophins for movement disorders. Finally, using 3-T MRI imaging techniques Dr Penn’s group is studying the development and resolution of hydrocephalus in shunted patients. Hydrodynamic principles are used to describe CSF motion, blood flow, and brain movement. The goal of this translational work is to design a “smart shunt” based on our new findings that allows better physiological control of ventricular size and pressure.


• Xiaoxi Zhuang PhD (Department of Neurobiology) is interested the role of the neurotransmitter, dopamine, in pathological behaviors and processes. He is investigating in how the specific aspects of reward are mediated by dopamine given its role in reinforcement learning and motivation that underlie addiction. Using transgenic mice with altered dopaminergic activity, his group found that elevated dopaminergic tone enhanced motivation without altering reinforcement learning. They are now interested in testing whether the phasic dopaminergic activity mediates reinforcement learning by examining, using genetic manipulation, the signaling pathways in striatal neurons that differentially process tonic versus phasic dopamine signals. In related work Dr. Zhuang is studying Parkinson’s disease, which is associated with the progressive, unexplained, loss of dopamine neurons. Because both oxidative stress, leading to protein misfolding, and dysfunction of the ubiquitin-proteasome pathway have been implicated. Zhuang’s group is investigating whether dopamine itself can cause oxidative stress and eventually dopamine neuron loss. They are testing whether loss or impairment of protective mechanisms (e.g. defects in transporting dopamine to vesicles, defects in protein folding and degradation pathways) prevent dopamine neurons from tolerating dopamine-mediated cellular stress that is not a problem under normal conditions, leading to dopaminergic cell loss. This is under investigation using in vivo transgenic mouse models. These studies on addiction and on Parkinson’s disease will not only reveal molecular targets for therapeutic interventions, but will also provide valid animal models to test potential therapeutic agents or approaches.



• Un Jung Kang MD has focussed his work on disease pathogenesis and motor complications in Parkinson’s disease (PD). His laboratory is currently studying the functions of two genes associated with recessive forms of PD, DJ-1 and PINK1 (PTEN-induced putative kinase 1). His group studies the role of these genes in mitochondrial function, oxidative stress and protein processing. He also studies their interaction with potential intrinsic vulnerability factors in SNpc neurons and with environmental toxins so that they may gain understanding of the common mechanisms of dopaminergic neuronal degeneration in both sporadic and genetic forms of PD. Dr. Kang is also interested in the mechanisms underlying motor response complications of dopaminergic replacement therapy, the current symptomatic treatment in PD. Dr. Kang has hypothesized that complications represent aberrant plasticity response. To investigate the underlying molecular mechanism he has developed mouse models of L-DOPA-induced dyskinesia and wearing-off. His group studies the role of NMDA receptor changes and alterations in the cellular signaling pathways leading to these changes. He also explores the specific anatomical structures that are important in mediating and therapeutic strategies that are capable if mitigating these changes.

• James Mastrianni MD PhD studies the pathogenesis of prion diseases, using a variety of experimental approaches, including cell culture, transgenic mouse models, yeast models, and organotypic brain slice preparations. Prion diseases, such as Mad Cow Disease, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, fatal insomnia, and chronic wasting disease of deer and elk are neurodegenerative diseases characterized by progressive dementia and motor abnormalities, that exhibit the unusual property of infectivity. The responsible infectious agent, called a prion, is unconventional and thought to be composed entirely of protein, predominantly of host brain-derived protein. The normal, brain-derived, cellular protein undergoes a conformational change to become infectious, and can bind to and convert other normal prion proteins to prions. Dr. Mastrianni’s lab is investigating what segments of the protein are critical to the process of prion propagation and conformational conversion, how specific mutations of the protein that are associated with familial prion disease produce prions, how different strains or phenotypes of prion disease are determined by the prion, how prions kill cells, and what other proteins may partner with prion protein to cause or modify prion disease. Their findings will help clarify how brain neurons die in prion diseases as well as other neurodegenerative diseases, such as Alzheimer’s disease and ALS.

• Brian Popko PhD is pursuing a better understanding of the molecules that are important to the development and maintenance of the peripheral nerve, using genetic mouse models as a key resource. Mutant and transgenic mouse strains have been particularly useful in the elucidation of in vivo functions of proteins and as authentic models for the study of human disease pathogenesis, and have the potential to be useful in the assessment of prospective therapeutic approaches. His research efforts have included the detailed phenotypic characterization of mutant strains of mice with behavioral, physiological, histological, biochemical, and molecular approaches. He is particularly interested in the interactions between the neuron and glial cells, and the role that these interactions play in the development and function of the nervous system. Alterations to the peripheral nerve myelin sheath underlie the peripheral neuropathy seen with Charcot-Marie-Tooth disease and Guillain-Barré syndrome.

• Christopher M. Gomez MD PhD concentrates his research program on the molecular and cellular mechanisms of neurodegenerative disease, with a particular focus on the means by which genetic mutations in ion channels or other essential proteins lead to dominantly inherited neurodegenerative diseases. In dominantly-inherited neurodegenerative diseases neuronal death arises because the genetic mutation alters, sometimes quite subtly, rather than abolishes the function of the disease protein. Altered function of ion channel molecules, proteins that are critical to neuronal activity, can impair neuronal viability through a variety of mechanisms. His laboratory pursues two primary project avenues, one on the genetics and pathogenesis of the slow-channel syndrome, a model disease of excitatory synaptic degeneration, the other representing a similar focus on genetically-determined spinocerebellar ataxias (SCA). Several forms of SCA are associated with mutations in ion channel genes. He also helps lead the Cooperative Ataxia Group, a national consortium of ataxia specialists devoted to enhancing clinical research in ataxia and launching clinical trials for the SCAs.
  
  The slow-channel syndrome is a chronic, usually congenital neuromuscular disease that causes progressive fatigability and weakness sometimes leading to death through respiratory failure. The disease is due to mutations in the genes that encode the acetylcholine receptor of the neuromuscular junction and thus is passed from parent to offspring. The mutations alter the acetylcholine receptor function making it leaky, which causes the neuromuscular synapse to become overloaded with sodium and calcium ions. The Gomez group has used both patient biopsy material and transgenic mouse models to determine that the degenerative process involves both pre and post synaptic structures and degenerative pathways that include the activation of several cysteine proteases. His group is currently developing therapeutic strategies using genetic approaches to selectively block these degenerative pathways in the muscle fibers.
  
  Spinocerebellar ataxia type 6 (SCA6) is a form of progressive cerebellar ataxia appearing in middle age that gradually leads to total incapacitation due to severe incoordination of all motor functions. Severe imbalance and gait instability progresses to wheelchair confinement. Oropharyngeal and upper limb incoordination disrupt the ability to perform activities of daily living including speaking, eating, and grooming. Erratic eye movements impair vision. The disease is associated with progressive degeneration of the cerebellar Purkinje cells and is due to a mutation in a gene encoding the major calcium channel of the cerebellum. The Gomez group has found that this mutation, which is a type called an expanded polyglutamine (polyQ) tract that is seen in other neurodegenerative diseases, alters the function of calcium channel protein in at least two fashions. First, as with the slow-channel syndrome, the expanded polyQ tract makes the calcium channel leaky, potentially leading to calcium overload of Purkinje cells and activation of degenerative pathways as is seen in that disorder. More importantly, they have discovered that the C terminal portion of the calcium channel that contains the polyQ tract is actually a form of nuclear signaling protein that is cleaved from the channel and transported to the nucleus. C terminal calcium channel proteins that contain the expanded polyQ tract are toxic to neurons and appear to cause damage by disturbing the DNA repair pathways. The Gomez lab is now delineating the normal and pathological actions of the calcium channel C terminus using biochemical cellular and genetic approaches.
  
  Click here to visit The University of Chicago Medical Center Ataxia Center website.

• Raymond Roos MD is investigating Theiler’s virus (TV), a mouse picornavirus that produces interesting neurological disease phenotypes. Certain strains from one TV subgroup produce a chronic persistent infection in mice in which autoimmune factors mediate a demyelinating disease. The demyelination caused by these strains provides one of the best experimental models for MS because of the similarity in their pathology and because the immune system appears to contribute to disease in both cases. Other strains from a second TV subgroup cause a motor neuron disease. The Roos lab is investigating Theiler's virus (TV)-induced disease in order to identify molecular determinants for demyelination and neurovirulence and the mechanisms involved. The basic aim is to define molecular determinants for the virus' biological behavior. The TV model is an especially valuable one for these studies because of the powerful molecular tools that are available, the interesting phenotypes of the strains, and the ease with which one can study this simple virus in a mouse (including various mouse mutant strains). With this goal in mind, the Roos lab has produced infectious cDNA clones from strains of the two different subgroups and generated recombinant and mutated viruses. The identification of the virus genes may not only clarify the pathogenesis of TV disease, but also lead to an understanding of genes important in the normal CNS and in human CNS disease states (such as MS and motor neuron disease).

• Brian Popko PhD has had a long-standing interest in the glial cells that are responsible for the formation of the myelin sheath. Over the past two decades his studies have contributed to our understanding of a number of myelin-specific proteins and lipids that play critical roles in myelin formation and maintenance, as well as in the development of the myelinating cells. These studies use a variety of molecular genetic approaches, including cell culture and mouse models.