WORCESTER, MA -The National Institutes of Health has awarded a $9.5 million grant to investigators at the University of Massachusetts Medical School to establish a Center for Collaborative Research in Fragile X, one of three centers designated by the NIH. Scientists at the centers will seek to better understand the Fragile X syndrome and its associated disorders in an effort to work toward developing effective treatments for the inherited illness. In total, the NIH awarded $35 million to the centers.
Professor of Molecular Medicine Joel D. Richter, PhD, is principal investigator on the 5-year grant that includes his colleagues Gary J. Bassell, PhD, professor of cell biology at Emory University, and Eric Klann, PhD, professor of neural science at New York University. Together, the trio will explore the underlying molecular basis of the Fragile X disorder, focusing on messenger RNA (mRNA) translational control.
"Fragile X syndrome arises when a single gene is inactivated," said Dr. Richter. "That indirectly causes protein synthesis in the brain to be elevated, which likely causes the disease. What we want to investigate is how that protein synthesis comes about and how rebalancing it can rescue or reverse the illness in mice so the animals no longer have the Fragile X syndrome."
Fragile X is the most common form of inherited intellectual and developmental disability. It can affect 1 in about 4,000 males or 1 in about 6,000 females. People with Fragile X suffer from intellectual disability as well as behavioral and learning challenges ranging from mild to severe. As many as 30 to 50 percent of people with the Fragile X syndrome also have disease features that are found on the autism spectrum.
An expansion of a CGG trinucleotide repeat in the DNA of the FMR1 gene causes the Fragile X syndrome. The Fragile X protein made from this gene is most commonly found in the brain and helps create and maintain plasticity. It is also needed for normal neurological development. The longer this CGG repeats the more severe the disabilities.
While the Fragile X protein has several functions in the brain, its primary role is to slow down the molecular machinery that translates mRNAs into mature proteins. Without the Fragile X protein, these machines run out of control. The result is excessive amounts of perhaps 1,000 or more different proteins in the brain of a Fragile X patient.
It is thought that this inability to repress mRNA translation, which in turn leads to an increase in neural proteins in the brains of Fragile X patients, somehow hampers normal synaptic function. But because the Fragile X protein interacts with so many mRNAs, and some proteins become more elevated than others, parsing which mRNA or combination of mRNAs is responsible for Fragile X is a daunting task.
Working together, Richter and his collaborates will investigate three molecules that have been shown to slow down mRNA translation in the absence of the FMR1 gene and restore biochemical balance, as well as cognitive and behavioral functioning, in mice. By learning which proteins are commonly impacted by all three molecules, they hope to identify possible therapeutic targets for Fragile X syndrome.
"In previous studies we've shown that we can reverse or rescue the Fragile X syndrome and restore nearly normal behavior and certain biochemical abnormalities in mice," said Richter. "We don't know if there are hundreds or thousands of proteins working in concert that cause the syndrome or whether there are only a few key proteins whose aberrantly excessive levels elicit disease characteristics. We want to investigate how this process works initially in mice and then in humans, which will hopefully lead to new treatments for this disease."
Other UMMS investigators on the study include John L. Sullivan, MD, professor of molecular medicine, and Manuel Garber, PhD, associate professor of molecular medicine and director of the bioinformatics core at UMMS.
The Centers for Collaborative Research in Fragile X was originally established in 2003 as a result of the Children's Health Act of 2000. Three centers were funded in 2013; in addition to the one at UMMS, other collaborative centers are at the University of Texas Southwestern Medical Center in Dallas and Emory University in Atlanta.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke are contributing funding and scientific expertise for the collaborative centers.
About the University of Massachusetts Medical School
The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, comprises the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. The Medical School attracts more than $240 million annually in research funding, placing it among the top 50 medical schools in the nation. In 2006, UMMS's Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator and the Blais University Chair in Molecular Medicine, was awarded the Nobel Prize in Physiology or Medicine, along with colleague Andrew Z. Fire, PhD, of Stanford University, for their discoveries related to RNA interference (RNAi). The 2013 opening of the Albert Sherman Center ushered in a new era of biomedical research and education on campus. Designed to maximize collaboration across fields, the Sherman Center is home to scientists pursuing novel research in emerging scientific fields with the goal of translating new discoveries into innovative therapies for human diseases.