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Science & TechnologyMODELING GLUTAMATERGIC SYNAPSES: INSIGHTS INTO MECHANISMS REGULATING SYNAPTIC EFFICACYMODELING GLUTAMATERGIC SYNAPSES: INSIGHTSINTO MECHANISMS REGULATING SYNAPTIC EFFICACY JEAN-MARIE C. BOUTEILLER, MICHEL BAUDRY, SUSHMITA L. ALLAM, RENAUD J. GREGET, SERGE BISCHOFF and THEODORE W. BERGER BME Department, University of Southern California Los Angeles, CA 90089, USA and Rhenovia Pharma, Mulhouse, France Rhenovia USC TeamRhenovia -USC Teams on Computer Modeling Effort
Two USC faculty members and the French drug discovery company Rhenovia Pharma have been awarded a biomedical research partnership by the National Institutes of Health to study the amino acid behind numerous diseases. Michel Baudry, a professor in the USC College department of biological sciences and principal investigator of the project, along with Theodore Berger of the USC Viterbi School’s department of biomedical engineering, will work with Serge Bischoff, the CEO of Rhenovia Pharma. The object of their research is a single neurotransmitter, the amino acid L-glutamate, which regulates biological systems. But even though scientists have known for decades that glutamate functions as a neurotransmitter and have found that numerous diseases, including possibly schizophrenia, are linked to “glutamatergic” transmission malfunctions, no drugs to treat these malfunctions yet exist, despite intense efforts. The researchers on this interdisciplinary study hope to learn enough to change this situation by using large-scale computer modeling to predict synergistic interactions within glutamate systems that might be targets for new drugs. Successful funding of this proposal is notable for the unique structure of the research team and for the novelty of the scientific approach, Baudry said. The grant will support joint research by the three partners for four years, with the total amount of funding reaching $2.3 million. Berger said the research effort is to develop a new technology of mathematical modeling, as well as computer simulation tools, to systematically explore molecular processes underlying glutamatergic synaptic transmission.. “This approach will not only provide an intimate understanding of the contribution of specific molecular events to synaptic plasticity and ultimately overall systems function, but it also will facilitate the design of better and safer therapeutic strategies for learning and memory impairments,” Berger said. According to Baudry. “The problem with glutamate in terms of pharmaceuticals is that this molecule is absolutely ubiquitous throughout the body,” he said. “What is therapeutic in one area can be toxic in another. The trick is to find a way to home in on the specific neural cells you want to affect, without disturbing the others.” One target the group will focus on is the hippocampal region, critical to learning and memory. Additionally, several neurological conditions, such as schizophrenia, are believed to be related to regulatory disruption of the glutamatergic system, Berger said. The research to be conducted by the USC and French research teams is centered on a detailed model of glutamatergic synaptic transmission, called EONS, first developed by Jean-Marie Bouteiller, a research assistant professor working in Berger’s laboratory. Bouteiller and Berger’s research on EONS was, and still is, supported by the USC Biomedical Simulations Resource, a center in the biomedical engineering department of the USC Viterbi School dedicated to the development of new methods for mathematically modeling physiological systems. Thus, said Baudry, the collaboration was a “natural,” and represents an example of the new emphasis on translational science, realized through collaborations that extend to, and include, industry, including researchers at USC, the University Louis Pasteur in Strasbourg and engineering and scientific staff at Rhenovia Pharma. Coordination and management are accomplished through weekly conference calls, e-mail and travel to and from Mulhouse, where the group recently held its first meeting.RHENOMS - PFG-1™: Bio simulation Biological systems consist of multitudes of interactions between complex mechanisms; pathologies often reflect the complexity of these interactions... Novel Drug discovery (DD) strategy for ALZHEIMER's and other brain diseases NEED TO INTEGRATE COMPLEXITY AND DIVERSITY FOR BETTER DRUGS The unmet medical needs, especially for Alzheimer's disease, are mostly due to the fact that all brain pathologies are extremely complex, multifactorial and dynamic. Furthermore, brain diseases are most probably of multiple origins and involve separate, physiological mechanisms, multiple pathways and neuronal/glial interactions. They might also affect dynamic features such as feedback/feed-forward regulations and cross-talk between extracellular and intracellular mechanisms. For these reasons, the conventional Drug Discovery (DD) approach followed by most pharmaceutical companies might not be sufficient to address the multiple facets of these diseases. In particular, the single-target, single-mechanism approach so suited for high-throughput screening may not result in optimal identification of candidate therapeutics. RHENOVIA INNOVATIVE APPROACH: SIMULATION PLATFORM FOR COGNITION Rhenovia's international team is developing an alternative DD strategy which takes into account most of these considerations: a) Complexity, by developing a unique technology which allows testing the pharmacological properties of a molecule based on its actions on physiological functions by integrating its dynamic interactions with the whole system; b) Multiple facets of the diseases, by searching for combinations of drugs that act simultaneously on multiple targets, and by identifying optimal combinations of two or more drug principles providing synergistic pharmacological effects. To this aim, we utilize a hybrid approach combining computer-assisted simulation of the molecular events taking place at excitatory glutamatergic synapses embedded into small neuronal networks and experimental validation. RHEDDOS SYSTEM: a new tool for pharma companieS This approach was first applied to the simulation of the events underlying the formation of long-term potentiation of synaptic transmission at hippocampal synapses, a phenomenon that is widely considered to represent a cellular mechanism involved in the formation of certain forms of learning and memory. With the RHEDDOS SYSTEM© (Rhenovia Drug Discovery Optimization Service), we offer to the pharma industry an interactive partnership. The objective is to use Rhenovia's technological platform to optimize the DD process. In the development phase, the goal is to improve the efficacy and maximize the therapeutic index of drug candidates by identifying synergistic combinations, as well as to create differentiation from competitors. Upstream, the service contributes to chose optimal targets, select most suitable lead families, predict the most adequate pharmacological profiling in order to reduce the number of animal experiments, minimize try-and-fail assays, accelerate the process and diminish the risks of failures. Executive Team: S. BISCHOFF, M. FAUPEL, J.-M. BOUTEILLER, T. BERGER, J. KREMERS, M. BAUDRY Contact: Dr Serge Bischoff, President - CEO
(sergebischoff@wanadoo.fr) Rhenovia Pharma, Maison du Technopole B.P. 2118, 40
rue Marc Seguin, France- 68060 Mulhouse Cedex. Office: +33 (0) 3 89 32 76 84. A full service brochure is available for the pharma companies upon request. Experimental ApproachExperimental Validation Platforms are validated by comparing simulated results with experimental results. In particular, the effects of various modulators affecting... |
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