Wells Center researchers "build" a better mouse model for neurofibromatosis type 2
Jan. 23, 2014
Mouse models of human disease are often key parts of biomedical research since they provide scientists a chance to understand the origins and progression of a disease -- and begin testing potential therapies -- in ways that may not be possible with tests in cell cultures in the petri dish.
But often there is no appropriate mouse model -- a line of mice bred or manipulated to develop a human disease or a close mouse counterpart. So researchers often will try to create the model they need.
This was the tactic recently taken by researchers in IU School of Medicine Department of Pediatrics, led by D. Wade Clapp, M.D., Chair and Richard L. Schreiner Professor of Pediatrics Molecular Biology and director of the Herman B Wells Center for Pediatric Research, who successfully created a more effective mouse model for neurofibromatosis type 2, or "NF2."
NF2 is a genetic disease that results in tumors known as "vestibular schwannomas" -- low-grade, or slow-growing, malignancies -- which frequently cause hearing loss in teenagers or people in their 20s by growing on the auditory nerve, which transmits sensory information from the inner ear to the brain.
The tumors also cause balance problems, numbness and other problems depending on their size and location, which may also include other parts of the body.
Dr. Clapp's team is the first to create a mouse model that develops tumors and hearing loss more closely resembling the disease in humans. Previous models, although a valuable resource for understanding disease pathogenesis and developing more effective therapeutic drugs, were ultimately limited for research purposes since they don't develop the same tumors as seen in humans to fully "mirror" the effects of NF2 in patients.
"This NF2 animal model will be a valuable tool with which to study disease pathogenesis and novel drugs targeting molecular pathways thought to be important to tumor development in NF2 and associated hearing loss," wrote the Department of Defense on a website devoted to congressionally directed medical research programs. (The project was funded by the DOD Neurofibromatosis Research Program's "Exploration - Hypothesis Development Award.")
To test their new breed, Dr. Clapp and his collaborators performed auditory brainstem response tests to determine when hearing loss occured in the mice. Despite the lack of structural defects in the inner ear, they found that the mice develop hearing loss beginning at 8 months of age, growing more serious over the course of the next two months -- the equivalent of losing the ability to hear normal conversation. A physical analysis of the mice also revealed the timing of the hearing loss matched the onset of NF2-style complications in the animals.
The discovery isn't the first feather in IU's cap related to treatment of this life-threatening genetic illness, with IU School of Medicine widely regarded as responsible for the first effective treatment for thetumors of neurofibromatosis type 1.
Additional members of the mouse model research team were Su-Jung Park, Ph.D., assistant research professor of pediatrics; Charles Yates, M.D., assistant professor of clinical otolaryngology-head & neck surgery; Jeff Gelhausen, an M.D./Ph.D. student.
Dr. Clapp is also a professor of microbiology and immunology and biochemistry and molecular biology at the IU School of Medicine.