August 19, 2005

Research into Parkinson’s disease enhanced by foundation’s grant

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Jeff Conn, Ph.D.

Research into Parkinson’s disease enhanced by foundation’s grant

Jeffrey Conn, Ph.D., professor of Pharmacology at Vanderbilt University Medical Center, has received a grant from the Michael J. Fox Foundation to find new chemicals for the treatment of Parkinson's disease.

The $200,000, two-year grant will support the use of high-throughput screening to identify compounds that can “turn up” the activity of a receptor that binds the neurotransmitter glutamate.

“We believe the activation of this receptor could reverse the pathological changes that occur in Parkinson's patients,” said Conn, director of the Program in Drug Discovery in the Vanderbilt Institute of Chemical Biology (VICB), and of the Program in Translational Neuropharmacology in the Department of Pharmacology.

Conn's project is one of seven funded this year by the foundation's “Target Validation” initiative, designed to accelerate the rate at which new Parkinson's therapies are brought to market. The foundation was established five years ago by actor Michael J. Fox after he was diagnosed with Parkinson's disease.

Target validation is an early step in drug discovery that uses compound screens and animal models to determine whether a molecular “target,” such as a receptor, plays an important role in disease and can be acted upon in a way that can relieve symptoms or slow progression of the disorder.

Conn and his colleagues have found that a particular glutamate receptor, mGluR7, regulates the transmission of signals through a nerve circuit in the brain involved in the control of voluntary movement. This is the circuit that becomes dysfunctional in Parkinson's disease.

However, they have not been able to find a compound that binds only to this receptor and does not activate other glutamate receptors elsewhere in the brain.

Their goal is to find compounds that bind to a secondary site on the receptor in a way that increases its activity when it binds to glutamate — much like a dimmer switch in an electrical circuit turns up the intensity of a light.

To aid the search for these compounds, also called an “allosteric potentiators,” the researchers will use the VICB's new high-throughput screening facility, which opened in March on the eighth floor of RRB.

The facility includes a “library” of 160,000 small molecules and about $1.5 million worth of computer-controlled, robotically accessible instruments that can test tens of thousands of samples per day for their ability to bind and/or modulate the activity of receptors or other target molecules.

In June, the facility was chosen to participate in the Molecular Libraries Screening Centers Network, an initiative of the National Institutes of Health (NIH). It received a $2 million pilot grant for the fiscal year beginning July 1.

The network was established last year as part of the NIH Roadmap initiative to help translate new scientific knowledge into “tangible benefits for people.”

Similarly, the Michael J. Fox Foundation initiative aims to increase the chances that “some of the most promising molecular targets … will yield new therapies for Parkinson's,” said Deborah W. Brooks, the foundation's president and CEO, said in a news release.