Mark Zervas, assistant professor of molecular biology, cell biology and biochemistry, won a $716,769 Department of Defense grant to study tuberous sclerosis, a developmental genetic disorder. Tuberous sclerosis occurs in approximately one in 6,000 live births and causes epilepsy, autism and cognitive impairment in a large percentage of affected people. The grant will go towards determining the stage of brain development during which treatment will be the most effective.
Zervas and Elizabeth Normand, a graduate student in the neuroscience program, have been studying tuberous sclerosis since January 2008. The Department of Defense is interested in researching this disease because it can provide insight on other neurological disorders, Zervas said. This is the second grant the department has awarded Zervas to study the disease.
Tuberous sclerosis is a genetic disorder caused by mutations in the genes TSC1 and TSC2, which code for proteins that bind together to form a complex and act as tumor growth suppressors. Affected individuals often are born with one mutated copy of the gene and acquire the second dysfunctional copy through random mutation. The TSC1 and TSC2 genes regulate a pathway that is implicated in a variety of human diseases.
Zervas uses a novel mouse model with a modified TSC1 gene to study the disease. By turning off the TSC1 gene in specific regions of the brain, Zervas and Normand seek to link specific brain regions with neurological manifestations of the disease. The Department of Defense project specifically studies the effects of turning off the TSC1 gene in the thalamus, an important area of the brain for sensory integration. By turning off the TSC1 gene at various points in the developmental pathway, Zervas and Normand also examine the point at which the disease most affects the brain during development.
Zervas' research will ideally yield important information about when and where administration of rapamycin - an immunosuppressant and anti-proliferative drug - is most effective in preventing and reducing the symptoms of the disease. This could be an important finding since continuous administration of the drug can have negative consequences due to its involvement in a number of biological processes. Rapamycin is used during organ transplants and cancer therapy, and Zervas said it is currently being tested for treatment of children with tuberous sclerosis.
Mustafa Sahin, assistant in neurology at Children's Hospital Boston, said the project is unique since Zervas is one of the only people in the field studying the thalamus.
The tuberous sclerosis project also has broader significance for the understanding of related syndromes. Normand became involved with the project due to her interest in neurological disease. The lessons learned about tuberous sclerosis can be applied to other disorders such as epilepsy, autism and cognitive deficits because they share a similar genetic cause. Zervas describes tuberous sclerosis as "not a niche disorder, but something that can apply more broadly to the study of complex brain disorders."