Neuroscience of Brain Disorders Awards

2010-2012

Angélique Bordey, PhD, Yale University School of Medicine
Cognitive Deficits in Tuberous Sclerosis Complex
Focusing on the cingulate cortex region of the brain, where learning and memory are stored, Dr. Bordey will seek to identify the cellular and molecular changes responsible for cognitive deficits associated with Tuberous Sclerosis Complex. She hopes to identify new biochemical pathways within the cells that are responsible for the deficits, and then attempt to treat them at the cellular and behavioral levels.

Rita Balice-Gordon, PhD, and Josep Dalmau, MD, PhD, University of Pennsylvania School of Medicine
Cognitive Deficits in Tuberous Sclerosis Complex
Dr. Balice-Gordon and Dr. Dalmau have recently discovered two novel diseases that occur when the immune system produces antibodies against excitatory glutamate receptors, called NMDA and AMPA receptors. They hope to determine how the antibodies alter the receptors and how changes in receptors lead to patients’ symptoms, including symptoms such as severe memory problems, seizures, and other cognitive and behavioral symptoms. Their work will provide a foundation for evaluating the best approaches to control the immune response and facilitate recovery.

Michael DeWeese, PhD, University of California, Berkeley
Probing the Cortical Mechanisms of Working Memory
Dr. DeWeese will develop a rodent model of working memory that can provide unprecedented access to the cerebral cortex during controlled behavior. With modern molecular and physiological tools originally developed for in vitro cellular and molecular studies, he plans to identify the specific cell types that exhibit sustained activity and to determine whether this heightened activity is driven mainly by an increase in excitatory synaptic input or a decrease of inhibitory synaptic input from other cortical neurons. This understanding could facilitate new cures or treatment for mental disorders associated with impaired working memory.

2009-2011

David Corey, Ph.D., Professor of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center
Allele-Selective Inhibition of Mutant Huntingtin and Other Triplet Repeat Proteins
Many neurological diseases, called triplet repeat diseases, are caused by mutant versions, or alleles, of a gene. Corey is investigating how these alleles can be inhibited without harming normal genes. During the grant period, Corey aims to strengthen the inhibitory factor and understand how selectivity is achieved, a key step before animal testing can begin. There is currently no cure available for such diseases, which include Huntington’s disease, and other strategies affect the normal as well as the mutant genes. Selective inhibition of the mutant gene might offer a treatment with fewer side effects for a wide range of neurological diseases.

Robert H. Edwards, M.D., Professor of Neurology and Physiology, University of California, San Francisco, School of Medicine
The Regulation of Mitochondrial Morphology by Alpha-Synuclein
The protein alpha-synuclein has a central role in Parkinson’s disease, but we do not yet fully understand its normal role in physiology, much less how it contributes to the disorder. To determine how alpha-synuclein functions in physiology and how it goes wrong in Parkinson’s, Edwards will study the mechanism by which synuclein affects mitochondria, an organelle long implicated in Parkinson’s. The project will seek to determine synuclein’s effects on mitochondria at a molecular and cellular level and will also test its role in neurons. The results are expected to suggest mechanisms that contribute to neural degeneration and may help find ways to prevent or arrest the degenerative process.

Mirjana Maletic-Savatic, M.D., Ph.D., Assistant Professor of Pediatrics, Section of Child Neurology, Baylor College of Medicine
Metabolomic Markers of Autism Spectrum Disorders
Maletic-Savatic seeks to determine if there is a metabolic signature that reflects the biological differences between different types of autism. She hypothesizes that genetic and environmental factors interact in autism and perturb the metabolic status of brain tissue. Using noninvasive proton magnetic resonance spectroscopy, she will image the brains of individuals who have one of three types of autism spectrum disorder but are on no medications or special diets. Metabolomic profiling of the human brain in vivo has not yet been attempted. Her goal is to develop and refine new signal processing algorithms that will help discern metabolic pathways that may be impaired in autism. The study, if successful, might significantly improve our ability to diagnose autism early and might also lead to improvements in the ability to detect brain metabolic abnormalities in other diseases.

John A. Wemmie, M.D., Ph.D., Associate Professor, Psychiatry, Neurosurgery and Neuroscience; and Vincent A. Magnotta, Ph.D., Associate Professor of Radiology, University of Iowa
Dynamics of Brain pH in Psychiatric and Neurological Disease
Recent studies suggest that pH in the brain may be more dynamic than previously appreciated. Wemmie and Magnotta’s preliminary data suggests that hydrogen ions might play a transmitter role and activate acid-sensing ion channels in the brain in psychiatric diseases such as anxiety disorders, and in neurological diseases including seizures, stroke and multiple sclerosis. The scientists plan to develop magnetic resonance imaging (MRI)-based strategies for measuring hydrogen ion concentration (pH) in the mouse and human brain. They seek to improve the ability to noninvasively monitor small and rapid pH changes in the human brain and to test the hypothesis that fear-evoking stimuli raise hydrogen ion concentration and alter brain pH. If their hypotheses are correct, the work would pave the way toward novel ways to diagnose, monitor and treat psychiatric and neurological illnesses.

X. William Yang, M.D., Ph.D., Associate Professor, Psychiatry and Biobehavioral Sciences, University of California, Los Angeles
Basal Ganglia Circuitry and Molecular Deficits in a Mouse Model of Tourette Syndrome
Tourette syndrome (TS) is a relatively common childhood-onset neuropsychiatric disorder characterized by multiple motor and vocal tics. Many TS patients also have other neurobehavioral conditions, such as obsessive compulsive disorder and attention deficit hyperactivity disorder. Although TS is thought to have a strong genetic component, the disease-causing mutant genes have not yet been elucidated. Neuropharmacological and imaging studies implicate basal ganglia dysfunction in TS, but how basal ganglia molecular and circuitry dysfunction may cause the behavioral deficits characteristic of TS and related conditions remains unclear. Yang will use mouse genetic approaches to test the hypothesis that developmental and/or functional imbalance of the two major basal ganglia neural circuits, the direct and indirect pathways, may underlie the behavioral manifestations of TS.

R. Suzanne Zukin, Ph.D., F.M. Kirby Professor in Neural Science and Neural Repair, Albert Einstein College of Medicine
Epigenetic Remodeling of Neuronal Genes in Global Ischemia
Zukin is exploring how brain insults such as stroke and open-heart surgery cause neurons to die, resulting in memory loss. To date there is no known treatment to halt the neurodegeneration associated with stroke. DNA is the genetic blueprint for all human cells; the reading and execution of the blueprint inside each cell is controlled by chemical markers attached to the DNA. The epigenetic code is altered in response to environmental cues and modulates the ability of each individual cell to transcribe the DNA. Zukin plans to map the epigenetic code represented by methyl groups or tags on the cells’ DNA to identify changes in the code produced by the brain insult. By creating a genome-wide map of the epigenetic code following stroke, Zukin and colleagues hope to uncover novel therapeutic strategies to ameliorate the neurodegeneration and memory loss caused by this devastating human condition.

2008-2010

Ilya Bezprozvanny, Ph.D., University of Texas Southwestern Medical Center
Deranged calcium signaling and neurodegeneration in Alzheimer's disease
Bezprozvanny's project focuses on whether abnormal neuronal calcium signaling contributes to neurodegeneration in Alzheimer's disease. If so, this "calcium hypothesis of Alzheimer's disease" would suggest that calcium blockers might be a potential treatment. He is examining the connection between abnormal calcium function of presenilin proteins, a major cause of the familiar form of Alzheimer's, and neuronal cell death.

Ming Guo, M.D., Ph.D., University of California, Los Angeles
Drosophila models of Parkinson disease
Using the fruitfly, Drosophila, Guo seeks to develop new models of Parkinson's disease to study genes identified with the disease and to identify cellular defects related to certain genetic mutations. She plans to dissect the molecular mechanisms that lead to mitochondrial dysfunction, which her research to date has shown is important in the disease.

Maria Karayiorgou, M.D., Columbia University Medical Center
A genetic mouse model of schizophrenia implicates miRNA biogenesis in disease Microdeletions on chromosome 22q11 account for up to 1 percent of schizophrenia cases and represent the only known recurrent mutation responsible for introducing new cases of schizophrenia in the population. Children with the 22q11 microdeletion show cognitive defects, and approximately one out of three go on to develop schizophrenia. Karayiorgou and colleagues have uncovered an alteration in the biogenesis of microRNAs (miRNAs) in the brain and plan to address whether this alteration contributes to the symptoms associated with the 22q11 microdeletion.

Bingwei Lu, Ph.D., Stanford University School of Medicine
Understanding the molecular basis of synaptic dysfunction in Alzheimer's disease
The earliest physiological defect observed in Alzheimer's disease is synaptic dysfunction, the failure of the cell-to-cell signals that underlie learning and memory. Using a combination of fly genetics and mammalian hippocampal neuronal culture, Lu will study how synaptic function and plasticity are regulated by a set of conserved signaling molecules that have been implicated in Alzheimer's disease-related processes.

Colleen A. McClung, Ph.D., University of Texas Southwestern Medical Center
The role of CLOCK and CCK in the development and treatment of mania
Mice with a mutation in the CLOCK gene show behaviors very similar to those of human bipolar patients in the manic stage, which are reversed by treatment with the mood stabilizer lithium. McClung's project has three goals. First, because the mutant mice have low levels of the peptide CCK, and lithium can to restore CCK levels to normal, she is exploring whether CCK may also be important in regulating mood. Second, she wants to determine how lithium restores CCK levels. Finally, she wants to determine if there are other genes in the dopamine cells that are controlled by CLOCK and are affected by lithium treatment.

Mark A. Tanouye, Ph.D., University of California, Berkeley
Neurological drug development using Drosophila seizure-suppressor mutants
The anti-seizure drugs currently used to treat epilepsy are not effective with all forms of the disease, and many such drugs have serious side effects. Seizure-suppressor genes for epilepsy have been discovered recently, and some have the potential to lead to new drug compounds. Using a new animal model developed in his lab for epilepsy, the fruitfly, Drosophila, Tanouye seeks to determine whether the newly discovered seizure-suppressor genes can lead to the development of novel anti-epileptic drugs.

Michael Bastiani, Ph.D., University of Utah
A genetic screen for genes influencing neuronal regeneration
Bastiani and colleagues have observed that neurons lacking the protein beta-spectrin break and regenerate repeatedly. Drawing on a recently developed RNA-interference screening technique, they plan to use this unique regeneration phenotype to examine every gene in the roundworm to determine which genes are involved in regeneration. The identification of these genes may further development of new therapeutic agents for many diseases caused by damage to the nervous system.

Andrew Dillin, Ph.D., Salk Institute for Biological Studies
Age-associated neuroprotection by insulin/IGF-1 signaling: from worm to mouse
Dillin's hypothesis is that the aging body continually produces proteins prone to aggregation, eventually leading to diseases such as Alzheimer's. He and his collaborators will examine how the worm C. elegans protects itself against toxic protein aggregation with age and will seek to evaluate whether mammals have the same protective mechanisms. The aim is to generate preliminary data for an ongoing collaboration to probe the link between aging and the progressive degeneration of neurons.

Andrew Lieberman, M.D., Ph.D., University of Michigan
Treatment of a polyglutamine neurodegenerative disease with synthetic bifunctional compounds that target misfolded proteins
Mutant proteins that misfold and aggregate are associated with motor neuron diseases and other chronic neurodegenerative disorders. Lieberman and colleagues, Jason Gestwicki, Ph.D., and William Pratt, M.D., focus on one such disease, Kennedy disease, a rare disorder that affects males, most often in middle adult life. Lieberman proposes to develop and test molecular compounds that may help prevent aggregation in mutated cells, manipulate protein interactions and define the interactions that lead to disease.

Janice Naegele, Ph.D., Wesleyan University
Brain grafts of GABAergic neurons derived from embryonic stem cells for treating temporal lobe epilepsy
Naegele and colleagues are seeking a way to replace injured neurons and suppress seizures in people with temporal lobe epilepsy. Their central hypothesis is that embryonic stem cell-derived GABAergic neuron grafts can incorporate into adult host brains and release the neurotransmitter GABA so as to inhibit seizures. During the grant period, they will genetically engineer stem cell lines, transplant neuronal cells into mice with seizures, examine whether these implants can integrate into the host brain circuits, and stimulate them to see how they react.

Lorna Role, Ph.D., State University of New York - Stony Brook
Neuregulin 1 regulation of nicotine-sensitive cortico-limbic circuits affected in schizophrenia
Many schizophrenic patients, as well as patients with other brain diseases, use smoking as a form of self-medication. Role and colleagues will examine whether nicotine-based therapeutics might mitigate the severity of some schizophrenic symptoms, such as memory deficits and poor attention span. The results will help identify molecular targets for potential therapies for schizophrenia and other brain disorders, including ADHD and Alzheimer's disease.

Charles Weitz, M.D., Ph.D., Harvard Medical School
Obesity, diabetes, and the arcuate nucleus circadian clock
The brain of every creature has a master circadian clock that drives daily rhythms of physiology and behavior. Other clusters of clock cells in the body also are known to exist, but their significance is unknown. Weitz will study whether clock cells in the arcuate nucleus, located in the hypothalamus, help with energy balance and glucose regulation. If this proves to be the case, the study will bring new insight into feeding behavior and glucose regulation and potential new strategies for drugs to treat obesity and diabetes.

C. Michael Crowder, M.D., Ph.D., Washington University School of Medicine
Identification of Genes Regulating Survival Following Hypoxic Insult in Caenorhabditis elegans
Stroke can cause lasting damage or death by depriving cells of oxygen, a condition called hypoxic injury. Yet nature seems to have developed ways to protect some cells from oxygen deprivation, as in certain hibernating fish and reptiles. Working with the nematode C. elegans, Crowder will search for genes that control the susceptibility of an organism and its nerve cells to hypoxic injury. Those genes will be potential therapeutic targets for prevention and treatment of stroke.

Guoping Feng, Ph.D., Duke University Medical Center
Understanding the Molecular and Cellular Basis of Obsessive-Compulsive Disorder Using a Novel Mouse Model
People with obsessive-compulsive disorder suffer from anxiety and often perform repetitive or ritualistic actions. Evidence suggests that OCD has a genetic basis, but no genes have yet been directly linked to it, and it is believed that multiple genes may be involved. Feng will use genetic approaches in mice to explore the pathogenic mechanisms of OCD and to identify potential new molecular targets for drug development. He is focusing on the possibility that OCD is related to synaptic defects.

Jill Morris, Ph.D., Northwestern University and Children’s Memorial Research Center
The Role of DISC1 in Neuronal Migration
People with mutations or changes in the gene called DISC1 (Disrupted in Schizophrenia 1) have an increased risk of developing schizophrenia. In people with schizophrenia, the DISC1 gene is mutated, and this mutation may cause neurons to grow abnormally during brain development. Morris will seek to determine the role DISC1 plays in brain development and how mutations or changes in the gene alter that development to cause schizophrenia and related disorders.

Jeffrey Noebels, M.D., Ph.D., and Richard Gibbs, Ph.D., Baylor College of Medicine
Profiling Ion Channel Genes in Autism
Ion channels allow cells to generate electrical signals in neurons and govern the precise patterns of signaling in brain networks. Noebels, Gibbs, and co-investigator Dan Burgess, Ph.D., hope to learn whether variation in genes encoding ion channels may give rise to autism, a poorly understood neurodevelopmental syndrome in children. Autism is also frequently associated with seizure disorders. The project will examine the exact gene sequence of all 250 human ion channels in groups of children with autism, and in those with autism and epilepsy. The project will be performed in partnership between Baylor’s Department of Neurology and Human Genome Sequencing Center.

Alexander Schier, Ph.D., Harvard University
Genetic Analysis of Sleep Disorders in Zebrafish
As many as 10 percent of Americans sleep poorly, but the genetic mechanisms that control sleeping and waking remain largely unknown. Narcolepsy has been related to the hormone hypocretin, but there’s no effective treatment for narcolepsy, and numerous other sleep disorders remain to be studied. Schier proposes to study sleep disorders using zebrafish, because they have hypocretin as well as brain structures similar to those that regulate sleep in humans. During the grant period, Schier will use forward genetic screening to look for the genes that regulate sleep and wakefulness. Once the relevant mutations are identified, it will become possible to clone those genes and translate the findings to mammals.

Richard Andersen, Ph.D., California Institute of Technology
A Human Cortical Prosthetic to Assist Severely Paralyzed Patients
Nearly 2.3 million Americans suffer paralysis from ALS, strokes, multiple sclerosis and other diseases as well as accidents. Inspired by prosthetic devices that use brain stimulation to help people with Parkinson's disease or deafness, Andersen's laboratory has made progress in developing a "brain-machine interface" to help people with severe paralysis. Andersen's device is unlike other efforts to facilitate movement by working on the motor cortex. Rather, it is a "cognitive cortical prosthetic" that would "read" the intentions of people with severe paralysis, enabling them to direct their movements. The McKnight award will help Andersen test the prosthetic with human patients.

John Brigande, Ph.D., Oregon Health & Science University; and Stefan Heller, Ph.D., Harvard Medical School
Stem-Cell-Based Therapy for Hereditary Hearing Loss
Hearing loss is the leading birth defect in the United States. Hearing impairment is frequently caused by malfunction of cochlear hair cells or the neurons that communicate with them. The ultimate treatment for hearing loss is to replace defective cells with healthy ones. Brigande and Heller are collaborating to establish a stem-cell-based treatment for hereditary deafness. They wish to learn if stem cells introduced into the developing inner ear of deaf mice by microinjection can give rise to healthy hair cells and improve auditory function after birth. The award fosters the intersection of two labs with diverse but complementary skills and enables them to take the first steps toward stem-cell-based therapy for human hearing loss.

William A. Catterall, Ph.D., University of Washington School of Medicine
Molecular Basis for Acquired Epilepsy in a Mouse Model
Building on previous work in his lab, Catterall now is applying discoveries on the basic function and molecular pharmacology of ion channels to the study of epilepsy, one of the most common neurological disorders. Epilepsy is actually many diseases, a fact that makes it difficult to understand and treat. Catterall's project focuses on one form, severe myoclonic epilepsy of infancy, or Dravet syndrome. Children with this disease develop seizures during their first year, followed by motor problems and mental retardation. Existing treatment is ineffective. Using a mouse model, Catterall will study ion channel genes and proteins in the brain to determine which are changed in the disease and what effects the alterations have. He will then seek to develop new drug therapies that prevent seizures in mice.

Sacha B. Nelson, M.D., Ph.D., and Gina G. Turrigiano, Ph.D., both of Brandeis University
A Physiological Genomics Approach to Understanding Rett Syndrome
Rett Syndrome, a common genetic cause of mental retardation and autism, is typically caused by the abnormal function of a single gene called MeCP2. Individuals generally develop normally for the first few months to a year of life, then regress. Deletion of all or part of MeCP2 in mice causes them to exhibit the symptoms of Rett Syndrome. Nelson and Turrigiano are conducting an electrophysiological analysis of the cortical circuits of mice that lack the gene to pinpoint where the change takes place. They are also identifying what genes go awry when MeCP2 is compromised and how. By combining physiological and molecular approaches, they hope to learn how the gene causes profound behavioral abnormalities despite only subtle changes in neuropathology. The disease pathway may also prove relevant to other disorders of brain development.

Gregory A. Petsko, Ph.D., and Dagmar Ringe, Ph.D., both of Brandeis University
Genetic Analysis of Tau
The protein tau has been implicated in nerve cell death in more than 20 brain diseases, including Alzheimer's, which are collectively known as tauopathies. Brains of patients with these diseases show aggregated filaments of tau, but it is not known how tau aggregation leads to cell death. Petsko and Ringe propose to study human tau expressed in yeast, which shows some of the same cellular effects from tau aggregation as human cells do. The scientists first seek to define the proteins and pathways that contribute to tau-induced toxicity, then to use those findings to search for novel drug candidates. These goals may be easier to achieve in yeast than in more complicated types of cells, since yeast is a very good system in which to do both genetic and biochemical experiments.

Kai Zinn, Ph.D., California Institute of Technology
Prion Aggregates, Synaptic Translation, and Neurodegeneration
Pumilio is an RNA-binding protein that represses protein translation. Zinn's lab has shown that Pumilio regulates expression of an essential translation factor on the postsynaptic side of neuromuscular junction synapses in flies. Pumilio also forms postsynaptic aggregates in mutant larvae, and overexpression of Pumilio is toxic. Based on preliminary results using yeast as a model system, the Zinn group speculates that Pumilio aggregates may take on prion-like conformations. Prions are protein-based genetic elements, and accumulation of a prion form of the human PrP protein is implicated in causing the neurodegenerative diseases kuru and BSE ("mad cow disease"). The award will enable Zinn's group to further evaluate Pumilio in the yeast and fly systems and attempt to determine if Pumilio can in fact function as a prion. This work may have implications for studies of mammalian brain function and dysfunction, since humans have a close relative of Pumilio that is expressed in the brain.