The Scripps Research Institute has been awarded $3.17 million over four years to develop compounds that will counteract disruptions of the human biological clock - the circadian rhythm that regulates our patterns of activity and rest over a 24-hour daily cycle. Circadian rhythm disruptions have been associated with sleep disorders, as well as bipolar disease and schizophrenia.
The grant, from the National Institutes of Health (NIH), was awarded to Thomas Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida.
The NIH also selected the Burris lab to receive a one-year award of $580,000 to develop compounds that might act against metabolic diseases such as diabetes and obesity and a one-year award of $243,000 to investigate a method of finding compounds that might lead to new treatments for diseases including cancer, inflammation, and diabetes.
"These grants will help move our research forward," Burris said. "For the four-year grant to study circadian rhythm disorders, we put together a group of four investigators at Scripps Florida - Pat Griffin, Ted Kamenecka, Andrew Butler, and myself - to investigate the widely accepted idea that circadian rhythms are involved in various disorders such as depression and schizophrenia. We have an initial lead that we believe will result in several new and more effective compounds."
Pat Griffin is chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida; Ted Kamenecka is associate scientific director of Scripps Florida's Translational Research Institute; and Andrew Butler is an associate professor in the Scripps Florida Department of Metabolism and Aging.
The one-year award to develop compounds for metabolic diseases, Burris said, is a seed grant that could grow into a new and much larger five-year grant involving the same group of Scripps Research scientists.
The Role of Nuclear Receptors
The work for all three grants is related to the Burris lab's work on specific "nuclear receptors," which might be modified with small molecules to counteract a number of disorders. The nuclear hormone receptor family is a large a group of protein molecules that recognize and regulate hormones as well as other natural substances in our body. As a result, these receptors control an organism's metabolism by activating gene expression.
Nuclear receptors make tempting drug targets because they can bind directly to DNA and activate genes through specific ligands-molecules that affect receptor behavior-such as the sex hormones, vitamins A and D, and glucocorticoids, which affect the body's response to stress. Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome.
Burris's research involves what are known as orphan nuclear receptors called RORs (retinoic acid receptor-related orphan receptors), a subgroup that plays a role in the expression of genes involved in the regulation of carbohydrate and fat metabolism, as well as circadian rhythm.
"The caveat is that since no one has ever developed ROR-related drugs, we don't know what the side effects might be," Burris said. "On the positive side, however, there is compelling evidence that these receptors are associated with these diseases, particularly the circadian rhythm disorders, and we have several compounds that can target these mechanisms and control them. We're on the cutting edge of this research."
In November of last year, Burris published a study in the Journal of Biological Chemistry that identified for the first time a novel mechanism that regulates circadian rhythm. The mechanism involved a specific ROR as well as another member of the nuclear receptor family.
Another Burris study, published around the same time in the journal ACS Chemical Biology, identified a novel compound acting on a pair of nuclear receptors that could provide new and potentially more effective therapeutic approaches to a range of metabolic diseases.
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