USC partners with French drug discovery company on computer modeling effort

April 24, 2009

A single neurotransmitter, the amino acid L-glutamate, regulates countless biological systems in animals ranging from worms and insects to human beings.

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.

Researchers on an interdisciplinary private-academic 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.

Two University of Southern California faculty members and the drug discovery company Rhenovia Pharma of Mulhouse, France, have been awarded a Biomedical Research Partnership (BRP) by NINDS of the NIH.

Michel Baudry, a professor in the USC department of biological sciences is the PI of the project. Theodore Berger, from the USC Vtierbi School's department of biomedical engineering is the Co-PI. They will work with Dr. Serge Bischoff, the CEO of Rhenovia Pharma.

Successful funding of this proposal is a notable achievement in the sense of the uniqueness of the structure of the research team, and in terms of the novelty of the scientific approach, says Baudry. The grant will support joint research by the three partners for four years, with the total amount of funding reaching $2.3M.

Berger says the research effort is to develop a new technology of mathematical modeling and computer simulation tools to systematically explore molecular processes underlying glutamatergic synaptic transmission, and the effects of those synaptic processes on multi-synaptic cellular dynamics, and ultimately, a small network of hippocampal neurons.

"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 also will facilitate the design of better and safer therapeutic strategies for learning and memory impairments."

While the ultimate goal is to enable effective development of drugs, the research proposed is basic understandings, according to Baudry. "The problem with glutamate in terms of pharmaceuticals is that this molecule is absolutely ubiquitous throughout the body. What is therapeutic in one area can be toxic in another. The trick is to find out 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, e.g., schizophrenia, are believed to be related to regulatory disruption of the glutamatergic system," says Berger.

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 Dr. Berger's laboratory.

Bouteiller and Berger's research on EONS was, and still is, supported by the USC Biomedical Simulations Resource (BMSR), a Center in the Biomedical Engineering Department of the Viterbi School of Engineering, dedicated to the development of new methods for mathematically modeling physiological systems."

Thus, says 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, not far from the Mulhouse home of Rhenovia, and engineering and scientific staff at Rhenovia Pharma itself.

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.

The following 'thinking points' define the strategy the USC-Rhenovia team will follow:

1. Pharmaceutical companies are realizing more and more that treatments for diseases of interest are not going to come in the form of a "silver bullet" -- a single drug that acts directly on the primary receptor and that suddenly "cures" everything.

2. Receptors have so many "regulatory" sites that it is clear that there are many, many places on the primary receptors that can be used to alter receptor function; perhaps several of these sites need to be occupied by drugs to produce the desired effect; these "modulatory" sites evolved for a reason.

3. An increasing number of studies are finding that agents that bind to these modulatory sites often can have little or no effect when used alone, but when used in combinations they can have large effects. These synergistic effects may represent the key to how to restore appropriate functioning of neural systems that are malfunctioning due to disease or aging. In other words, several of the regulatory sites need to be occupied simultaneously, and re-establishing normal synaptic transmission will require finding appropriate levels of activation (drug concentration) of those multiple sites simultaneously.

4. Finally, and critically: finding such synergistic effects would be very difficult if not impossible to achieve experimentally. But while computationally intensive, computer simulations could potentially create a map to guide experimenters. This will require a comprehensive model, with most of the sites for regulating both the input (presynaptic mechanisms) and the output (postsynaptic mechanisms) of key neurotransmitter systems identified correctly, lots of computing power, and expertise with the systems.

University of Southern California

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