“Anxiety is among the most common psychiatric disorders and affects about 20 million American people,” says Lei, assistant professor in the medical school’s Department of Pharmacology, Physiology & Therapeutics. “Everyone at some time or another feels anxious, sometimes enough to warrant medical treatment. But even though there are drugs which can be used to treat anxiety, we are still achieving only modest success in treating and curing this disorder.”

Lei explains that our limited successes in treating anxiety are mostly because scientists still do not have a complete picture of the molecular and nervous system mechanisms that produce this disorder. Moreover, most available medications have side effects—sometimes very serious—or they create problems with tolerance or dependence.

“So it is of significant interest to further explore these anxiety-producing mechanisms in the brain,” says Lei, who grew up in central China and obtained his medical degree there. “Of course, we expect our research to lead to novel and much more effective therapeutic strategies to deal with anxiety.” Lei and his team of researchers at the UND medical school are testing the roles of the neuropeptide, cholecystokinin (CCK), in anxiety. Peptides are relatively short chains of amino acids (ingredients in the molecular makeup of our DNA and proteins). Proteins such as DNA are formed from very long peptide chains. Neuropeptides are protein-like molecules made in the brain.

CCK was originally discovered in the gastrointestinal tract, but it is the most abundant neuropeptide in the brain. It has been known for decades that application of CCK to animals and humans can induce anxiety, but no one knows exactly how it works.

“We want to figure out how CCK increases anxiety,” says Lei, whose research center is part of the medical school’s free-standing Neuroscience Laboratory. “After we know the mechanisms by which CCK increases anxiety, eventually we will try to find out whether drugs that reduce the function of CCK system in the brain can be used to treat anxiety.”

That means Lei and his team must pry open the secret of how anxiety is produced. “There is some recently compelling evidence that anxiety is related to an increase in the function of glutamate system in the brain,” he says. Glutamate—yes, the same compound that’s in flavor-enhancing ingredient MSG—is an excitatory neurotransmitter in the brain. Glutamate can be released from one neuron and activate glutamate receptors on another neuron to make the second neuron more excited. Increases in the excitability of neurons in the brain can produce anxiety.

“Because CCK is a natural substance in the brain, we want to test whether and how CCK changes the functions of glutamate in the brain,” Lei says. “We want to test the hypothesis that CCK increases anxiety by enhancing glutamate release and up-regulating glutamate receptor functions. We will also test whether down-regulation of the functions of CCK system such as using CCK receptor inhibitors or knocking out the genes for CCK and CCK receptors reduces anxiety.”

“Basically, we are trying to find out whether modulation of CCK system can serve as a novel way to treat anxiety,” Lei says.

Lei’s five-year NIH RO1 grant will support several researchers. The Research Project Grant (R01) is the original and historically oldest grant mechanism used by NIH. The R01 provides support for health-related research and development based on the mission of the NIH.

The NIH awards R01 grants to organizations of all types (universities, colleges, small businesses, for-profit, foreign and domestic, faith-based, etc.). The R01 mechanism allows an investigator to define the scientific focus or objective of the research based on a particular area of interest and competence. Although the Project Director/Principal Investigator writes the grant application and is responsible for conducting the research, the applicant is the research organization.

Contact Juan Pedraza, director of communications School of Medicine and Health Sciences University of North Dakota (701) 777-6048 jpedraza@medicine.nodak.edu