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Outstanding Achievement in Schizophrenia Research

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

Series E. 2; 5.9

2014 Prizewinner:
David Braff, M.D.
 – University of California, San Diego School of Medicine – Watch Video

David Braff M.D. named Lieber Prize winner

David Braff MD, Distinguished Professor at UCSD’s Department of Psychiatry has been named this year’s Lieber Prize winner by the National Brain and Behavior Research Foundation (NBBRF) and the National Association for Research in Schizophrenia and Depression (NARSAD). This Prize is given to an outstanding neuropsychiatric researcher who has enhanced our fundamental understanding of schizophrenia, a devastating no fault heritable clinical brain disorder affecting 1% of the world’s population. Schizophrenia causes psychosis, cognitive dysfunction and profound disability in many patients. It also affects the families of the patients, since the disability-often strikes early in young adult life. Past Lieber Prize winners include two Nobel Laureates and many other world leading distinguished neuroscientists. The Award will be presented at a scientific meeting, ceremony and dinner in New York at the NBBRF-NARSAD Annual Gala at Lincoln Center in late October.

Dr. Braff has pursued and extended our understanding of schizophrenia via a number of major research projects. The Consortium on the Genomics of Schizophrenia (COGS) is a 30 million-dollar 10 year NIMH-funded consortium on the neurocognitive, neurophysiological, neural circuit and dysfunctional genomic architecture of schizophrenia. Dr Braff has been Principal Scientist and Director of this 7-site study: COGS 1 examined clinical features, neurocognitive and neurophysiological, and other familial endophenotypes or biomarkers in schizophrenia patients and their families as well as healthy control subjects. The follow up COGS 2 is studying 2500 schizophrenia patients and case-control subjects. Genomic and related methods include extensive behavioral, candidate gene, genome wide association, sequencing, methylation and stem cell projects from COGS and UCSD grants. This has led to an increased understanding of both the neural network and underlying genomic network bases of schizophrenia and has enhanced our understanding of risk and vulnerability markers which may provide targets for very early intervention and even, in the longer run, prevention. This neurodevelopmental psychotic process starts early in life but usually manifests itself in late teenagers and young adults. In addition, because of the underlying complex neural and genomic networks that have been identified by this work and the studies of other scientific projects, we have hope of finding novel therapeutic targets for pharmacological and sensory training- cognitive behavioral therapies for this devastating disorder.

Dr. Braff also has conducted longstanding translational (TRANS) and genomic studies over 30 years of continuously funded projects supported by NIMH, NARSAD and the Brain and Behavior Foundation. This research, conducted with many essential colleagues, including TRANS Co-PIs Mark Geyer, Ph.D. and Neal Swerdlow, M.D. Ph.D., has led to cross-species translational advances in understanding the neurobiology of schizophrenia and created powerful tools for screening candidate antipsychotic compounds to treat schizophrenia. Braff has also Directed the VA VISN 22 Mental Illness Research Center Clinical Neuroscience and Genomics Project, which provides crucial infrastructure and intellectual support for this work.

In recent years, Dr. Braff, a NARSAD Distinguished Investigator, has consistently been ranked by “ISI” in the top half of the top percent of all cited neuropsychiatric researchers based on the frequency with which his 300 publications are cited. He has also been awarded the Warren Award from the International Congress of Schizophrenia, the Inspiration Pioneer Research Award from NAMI, the Dean Award from the American College of Psychiatrists and the Marmor Award from the American Psychiatric Association, all given to honor an outstanding neuropsychiatric researcher. Dr. Braff’s colleagues at UCSD have included crucial contributions and context from TRANS Co-PIs, Mark Geyer Ph.D. and Neal Swerdlow MD Ph.D., Department Vice Chair (Also Deputy Director of COGS) as well as more recent faculty appointees Gregory Light, Ph.D (UCSD COGS Director and San Diego VA VISN 22 MIRECC Director) and Tiffany Greenwood, Ph.D. (Genetics And Statistical Genetics Lead Scientist) and many others.

Dr. Igor Grant, Chair of the Department commented, “Professor David Braff has been at the forefront of research into the neurobiology of schizophrenia. Beginning with observations on neurophysiologic biomarkers related to aberrant attentional and other cognitive mechanisms in those afflicted with schizophrenia, his work has progressed to linking such biomarkers to genetic underpinnings of this serious disorder, which affects 1% of our population, and causes great disruptions both for the person affected, and their families and loved ones. Professor Braff’s innovative work has opened better understanding of the interplay of genetic and neurodevelopmental factors in the evolution of schizophrenia, as well as promise of specific diagnostic markers that may help with early identification of people vulnerable to this disorder, at a time when preventive strategies may be most useful. As such his work will inform both improved treatment and prevention. Dr. Braff has also been a generative mentor to younger scientists, a fine educator, and helped the Department establish a modern inpatient psychiatric unit to care for people with severe mental disorders. The Department is very proud that Professor Braff was recognized with the Lieber Prize, reserved for the very finest psychiatrist scientists.”

https://youtu.be/c1_FtkMLJc4

“We are entering a new era of the neuropsychiatric and genomic revolutions, where advanced bioinformatics and other evolving technologies will help us to integrate brain, behavioral and genomic data about schizophrenia that we only imagined was possible in the past. Receiving this prize will serve to enhance all of our endeavors.”

 

Patrick F. Sullivan, M.D., Karolinska Institutet & University of North Carolina – Watch Video

Patrick F. Sullivan Awarded 2014 Lieber Prize for Outstanding Achievement in Schizophrenia Research

Patrick F. Sullivan, MD, FRANZCP, M. Hayworth & Family Distinguished Professor of Psychiatry and Professor of Genetics and Psychiatry at the University of North Carolina School of Medicine, is one of two researchers awarded the 2014 Lieber Prize for Outstanding Achievement in Schizophrenia Research.

The $50,000 cash award from the Brain & Behavior Research Foundation is given in recognition of a research scientist who has made distinguished contributions to the understanding of schizophrenia. It rewards past achievement and provides further incentive for an outstanding working scientist to continue to do exceptional research into the causes, prevention, and treatment of schizophrenia.

“The 2014 Outstanding Achievement Prize winners have dedicated their lives to solving some of the most intractable psychiatric problems in order to improve the lives of millions of people and their families,” said Jeffrey Borenstein, MD, CEO of the Brain & Behavior Research Foundation. “We applaud their past and future accomplishments.”

As a psychiatric geneticist, Dr. Sullivan works to decode the molecular and cellular consequences of genetic variations underlying schizophrenia. He heads large, multinational projects across a range of disorders, dividing his time between Sweden, where he is a Professor at the Karolinska Institutet, and UNC, where he is the Director of the Center for Psychiatric Genomics.

As founder and lead investigator of the Psychiatric Genomics Consortium (PGC), Dr. Sullivan directs 300 scientists from 70 institutions in 19 countries who are conducting mega-analyses, involving 90,000 participants, of genetic risk for schizophrenia, depression, autism, bipolar disorder and attention-deficit hyperactivity disorder. He is also the principal investigator for a Swedish genetic study of 10,000 patients with schizophrenia and bipolar disorder, one of the few projects looking into the impact of environmental factors in these disorders.

http://www.youtube.com/watch%3Fv%3DPzoEgKv5yKQ    Feb 5, 2015

A Stockholm Psychiatry Lecture held at Karolinska Institutet Feb 3 2015 by Prof. Patrick F Sullivan, UNC and KI.

http://www.dana.org/Briefing_Papers/Schizophrenia__Q_A_with_Patrick_F__Sullivan/Jul 14, 2015

Baby steps may become giant steps in the next ten years for schizophrenia, an illness which impacts an estimated 2.4 million Americans

 https://youtu.be/uJmA0gGTUnk 

“It is my deep hope that the work that led to my selection of this prize will continue so that we can greatly expand our knowledge of the genetic basis of schizophrenia so that these new findings will, in turn, lead to advances that improve the lives of people living with schizophrenia and other serious mental disorders.”

SIDNEY R. BAER, JR. PRIZE FOR INNOVATIVE AND PROMISING SCHIZOPHRENIA RESEARCH

Gregory Light, Ph.D.
University of California, San Diego

https://youtu.be/XqtcBkyz7vE

“This award strengthens my resolve to continue to develop treatment strategies that will ameliorate, prevent, and perhaps even cure schizophrenia and related psychotic illnesses in the next stages of my career.”

Stephan Ripke, M.D.
Broad Institute

https://youtu.be/nMfKsWFdM-k

“As a result of the immense collaborative efforts of the PGC, I believe that we are now on the path towards making seminal discoveries into the biology of this devastating disease. New therapeutic targets are imminent and the support of this prize will have a great impact on realizing this goal.”

 

Colvin Prize for Outstanding Achievement in Mood Disorders Research:

Wayne C. Drevets, M.D.
Janssen Pharmaceutica

https://youtu.be/xs7c3u3_pjk

“This prize not only affirms the significance of our past work, it also inspires and invigorates our current and future research, which we hope will improve the lives of people affected by bipolar disorder by leading to the discovery and development of new treatments.”

Fritz A. Henn, M.D., Ph.D.
Cold Spring Harbor Laboratory

https://youtu.be/-HVF-Lxpx14

“That my peers feel our work merits recognition is the greatest reward after a lifetime of work aimed at understanding and better treating major mental illness.”

2013 Marc G. Caron, Ph.D.
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Duke University School of Medicine
2012 Michael J. Owen, M.D., Ph.D.
Video Clip
Cardiff University
2012 Michael O’Donovan, M.D., Ph.D.
Video Clip
Cardiff University
2011 Carol A. Tamminga, M.D.
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UT Southwestern Medical Center at Dallas
2011 Joel E. Kleinman, M.D., Ph.D.
Video Clip
National Institute of Mental Health (NIMH)
2010 Ming T. Tsuang, M.D., Ph.D., D.Sc.
Video Clip

 

Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience

2014 Prizewinner:

Richard L. Huganir, Ph.D. – The Johns Hopkins University School of Medicine – Watch Video

Department Affiliation: Primary: Neuroscience; Secondary: Biological Chemistry; Howard Hughes Medical Institute
Degree: Ph.D., Cornell University
Rank: Professor/Director, Department of Neuroscience

Regulation of Neurotransmitter Receptors and Brain Function in Heath and Disease

Neurotransmitter receptors mediate signal transduction at the postsynaptic membrane of synaptic connections between neurons in the nervous system. We have been studying the molecular mechanisms in the regulation of neurotransmitter receptor function. Recently we have focused on glutamate receptors, the major excitatory receptors in the brain. Glutamate receptors can be divided into two major classes: AMPA and NMDA receptors. AMPA receptors mediate rapid excitatory synaptic transmission while NMDA receptors play important roles in neuronal plasticity and development. Studies in our laboratory have found that both AMPA and NMDA receptors are multiply phosphorylated by a variety of protein kinases. Phosphorylation regulates several functional properties of these receptors including conductance and membrane targeting. Recent studies in our lab have demonstrated that the phosphorylation of AMPA receptors is regulated during cellular models of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). Moreover, phosphorylation of the AMPA receptor GluR1 subunit is required for the expression of these forms of plasticity and for the retention of spatial memory and also regulates emotional memory formation and erasure.

We have also been examining the mechanisms of the subcellular targeting and clustering of glutamate receptors at synapses. We have recently identified a variety of proteins that directly or indirectly interact with AMPA and NMDA receptors. We have found a novel family of proteins that we call GRIPs (Glutamate Receptor Interacting Proteins) that directly bind to the C-termini of the GluR2/3 subunits of AMPA receptors. GRIPs contain seven PDZ domains, protein-protein interaction motifs, which crosslink AMPA receptors to each other or link them to other proteins. In addition, we have found that the C-termini of GluR2 also interacts with the PDZ domain of PICK1, a protein kinase C-binding protein that is found at excitatory synapses. The GluR2 subunit also interacts with the NSF protein, a protein involved in the regulation of membrane fusion events. These AMPA receptor interacting proteins are critical in the proper membrane trafficking and synaptic targeting of these receptors. We have shown that the binding of PICK1 and GRIP is required for a specific form of LTD in the cerebellum that is a cellular model for motor learning. Moreover, we have found that this receptor complex is critical for hippocampal LTP and LTD and spatial learning.

In addition to these studies on AMPA receptors, we have been characterizing a separate NMDA receptor associated protein complex that is important in synaptic targeting and downstream signaling of NMDA receptors. We have identified an excitatory synapse specific rasGAP, which we call synGAP that regulates synaptic Ras signaling and has profound effects on synaptic plasticity.

Importantly, recent evidence has implicated glutamate receptor associated complexes in several neurological and psychiatric disorders including Alzheimer’s disease, schizophrenia, autism, mental retardation as well as in chronic pain and drug addiction.

In summary, we have examined the molecular mechanisms underlying the regulation of neurotransmitter receptor function. Our studies have suggested that regulation of receptor function may be a major mechanism for the regulation of synaptic plasticity in the nervous system in health and disease and may be an important determinant of animal behavior.

Representative Publications:

  • Volk, L.J., Bachman, J.L., Johnson, R., Yu, Y., Huganir, R.L. (2013) PKM-Z is not required for hippocampal synaptic plasticity, learning and memory. Nature 493(7432): 420-3. Pub Med Reference
  • Thomas, G.M., Hayashi, T., Chiu, S.L., Chen, C.M., Huganir, R.L. (2012) Palmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking. Neuron73(3):482-96. Pub Med Reference
  • Makuch, L., Volk, L., Anggono, V., Johnson, R.C., Yu, Y., Duning, K., Kremerskothen, J., Xia, J., Takamiya, K., Huganir, R.L. (2011) Regulation of AMPA receptor function by the human memory-associated gene KIBRA. Neuron 71(6):1022-9. Pub Med Reference
  • Makino, Y., Johnson, R.C., Yu, Y., Takamiya, K., Huganir, R.L. (2011) Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor. Proc Natl Acad Sci USA. 108(20):8450-5. Epub 2011 May 2. Pub Med Reference
  • Mejias, R., Adamczyk, A., Anggono, V., Niranjan, T., Thomas, G.M., Sharma, K., Skinner, C., Schwartz, C.E., Stevenson, R.E., Fallin, M.D., Kaufmann, W., Pletnikov, M., Valle, D.,Huganir, R.L., Wang, T.  (2011) Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism. Proc Natl Acad Sci USA. 108(12):4920-5. Pub Med Reference 
  • Clem, R. and Huganir, R.L. (2010) Calcium-permeable AMPA receptor dynamics mediate fear memory erasure, Science 330(6007): 1108-12.  Pub Med Reference
  • Hayashi, T., Thomas, G., Huganir, R.L. (2009) Dual palmitoylation of NR2 subunits regulates NMDA receptor trafficking. Neuron 64(2): 213-226. Pub Med Reference
  • Lin, D.T., Makino, Y., Sharma, K., Hayashi, T., Neve, R., Takamiya, K., Huganir, R.L. (2009) Regulation of AMPA receptor GluR1 subunit extrasynaptic insertion events by 4.1N, phosphorylation and palmitoylation. Nat. Neurosci. 12(7): 879-87.� PMCID:� PMC2712131. Pub Med Reference
  • Sia, G.-M., Beique, J.-C., Rumbaugh, G., Cho, R., Worley, P.F., Huganir, R.L. (2007) Interaction of the N-terminal domain of the AMPA Receptor GluR4 subunit with the Neuronal Pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 55(1): 87-102. Pub Med Reference
  • Steinberg, J.P., Takamiya, K., Shen, Y., Xia, J., Rubio, M.E., Yu, S., Jin, W., Thomas, G.M., Linden, D.J., Huganir, R.L. (2006) Targeted In Vivo Mutations of the AMPA Receptor Subunit GluR2 and its Interacting Protein PICK1 Eliminate Cerebellar Long-Term Depression.Neuron. 49(6): 845-60. Pub Med Reference
  • Chung, H.J., Steinberg, J.P., Huganir, R.L. and Linden, D.J. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300:1751-1755, 2003.Pub Med Reference
  • Lee, H-K., Takamiya, K., Han, J-S., Man, H., Kim, C.-H., Rumbaugh, G., Yu, S., Ding, L., He, C., Petralia, R.S., Wenthold, R.J., Gallagher, M., and Huganir, R.L. (2003) Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112:631-643.  Pub Med Reference
  • Lee, H.K., Barbarosie, M., Kameyama, K., Bear, M.F., and Huganir, R.L. (2000) Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature405:955-959. Pub Med Reference
  • Ehlers, M.D., Zhang, S., Bernhardt, J.P., and Huganir R.L. (1996) Inactivation of NMDA receptors by direct interaction of calmodulin with NR1 subunit. Cell 84:745-755. Chung, H.J., Steinberg, J.P., Huganir, R.L. and Linden, D.J. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300:1751-1755, 2003. Pub Med Reference

GOLDMAN-RAKIC PRIZE FOR OUTSTANDING ACHIEVEMENT IN COGNITIVE NEUROSCIENCE

https://youtu.be/4alesBVcM3s

“This has been my life long career goal—to understand how memory is encoded in the brain and how these mechanisms are disrupted in cognitive disorders. I am honored to be associated with Dr. Goldman- Rakic’s legacy.”

2013 Karl Deisseroth, M.D., Ph.D.
Video Clip
Stanford University
2012 Larry R. Squire, Ph.D.
Video Clip
University of California, San Diego
2011 Michael E. Goldberg, M.D.
Video Clip
Columbia University/NYSPI
2010 Robert Malenka, M.D., Ph.D.
Video Clip
Stanford University
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