Characterization of a Novel Humanized Mouse Model of Neurofibromatosis
Abstract
Many different gene mutations are known to cause neurofibromatosis type 1 (NF-1). To date, most studies aimed at understanding the ways in which mutations in the NF1 gene lead to the symptoms experienced by NF patients have used genetically engineered mouse models that lack a single or both copies of the NF1 gene. This approach has provided substantial insights into NF1 mechanisms in normal development and NF. Other forms of NF arise when the NF1 protein is produced, but changed at one or a few amino acids. These mutations tend to alter the function or stability of the NF1 protein, and why these mutations lead to NF is much less well understood. One surprising aspect of these small mutations is that, despite such a minimal change in the protein, their presence produces some of the same symptoms as complete loss of NF1 protein. NF1 is a fairly large protein, with many distinct domains that likely have different functions, and the effect of these minimal mutations suggests that critical functions are assigned to particular portions of the protein. Our application will use a newly generated mouse model with such a mutation. It is a known patient mutation and results in some of the symptoms associated with NF, including learning and cognitive challenges. We propose here to characterize how this mutation could lead to these effects by altering brain development in this new mouse model. This research will increase our knowledge related to both patients with this specific type of mutation and the greater population of NF patients. A clearer understanding of how this particular mutation is able to produce the symptoms seen in most NF cases may point to a common protein partner affected by this mutation or a general mechanism that could be pursued as a more effective therapeutic approach, with this model potentially serving as a platform to test such therapies. As an Idea grant stage proposal, it is difficult to estimate the projected time to achieve a patient-related outcome, as it will depend on our findings from this study. If successful, our proposed work would advance the field of research by provided a new and validated mouse model for researchers in this area to test the impact of this mutation in multiple types affected by NF.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810207
Entities
People
- Anthony P Barnes
Organizations
- Oregon Health & Science University
- United States Army