Improving Cognitive and Behavioral Function in NF1 Genetically Engineered Mice

Principal Investigator: GUTMANN, DAVID H
Institution Receiving Award: WASHINGTON UNIVERSITY
Program: NFRP
Proposal Number: NF093033
Award Number: W81XWH-10-1-0884
Funding Mechanism: Investigator-Initiated Research Award
Partnering Awards:
Award Amount: $855,850.41


Managing the cognitive and behavioral abnormalities affecting children with neurofibromatosis type 1 (NF1) poses one of the most challenging clinical issues for physicians and parents. Children with NF1 have difficulties with specific learning tasks (spatial memory and learning) as well as attention, which limit their school performance. In addition, children with NF1 are also prone to the development of brain tumors (optic gliomas), and cancer treatment in these patients is associated with further impairments in learning and memory.

In an effort to galvanize progress in this critical area, we have assembled a cross-disciplinary team of researchers with expertise in NF1 biology and rodent behavioral testing to fully characterize the learning and behavioral abnormalities in laboratory-generated Nf1 mutant mice, and to determine whether conventional treatments or biologically-based therapies might improve these NF1-associated learning and behavioral deficits. We have recently shown that novel Nf1 genetically-engineered mice with brain tumors, developed in our laboratory, exhibit impaired learning and behavioral abnormalities, similar to children with NF1.

In this grant, we propose to employ our Nf1 genetically-engineered mice to determine which behavioral deficits most closely resemble those observed in children with NF1. We will use these experiments to develop a sensitive battery of reliable behavioral tests to efficiently evaluate the efficacy of various therapeutic treatments on the learning deficits and abnormal behavior in these mice. Since children with NF1-associated optic gliomas may experience further declines in cognitive function following brain tumor therapy, we plan to determine whether brain tumor treatment exacerbates the learning deficits and abnormal behaviors in Nf1 genetically-engineered mice.

Finally, we propose to determine whether the learning and behavioral abnormalities observed in these mice can be improved following conventional and biologically-based treatments.

Collectively, the experiments proposed in this study will provide suitable preclinical platforms to evaluate treatments aimed at reducing the learning and behavioral difficulties affecting children with NF1, and represent a novel use of genetically-engineered mice to develop strategies aimed at treating non-tumor clinical problems in people with NF1.