Neurofibromatosis type 1 is one of the most common monogenic developmental disorders, affecting ~1 in 3,500 individuals worldwide. Some form of cognitive or neuropsychiatric dysfunction is present in approximately 50-80% of individuals with NF1, and these are often considered the major causes of lifetime morbidity. The neurofibromin protein (Nf1) directly inhibits Ras signaling, but also affects several other signaling cascades (possibly indirectly). The complexity of the signaling cascades implicated in neurofibromatosis 1, combined with the lack of drugs to target Nf1 directly, highlights the pressing need for new approaches to target NF1 phenotypes. Uncovering genetic modifers of neurofibromatosis 1-related cellular dysfunction would provide potential new targets for treating this disorder. This project will focus on hyperactivity and repetitive behaviors in Drosophila loss of function nf1 mutants. The large effect size of these behavioral deficits will enable their use it as a readout to unravel both the in vivo molecular and circuit functions of the neurofibromin protein in a powerful genetic model organism.
Specific aims will investigate how Nf1 loss of function affects hyperactivity/repetitive behaviors, test the signaling and genetic interactions underlying Nf1 function, probe its role in a putative signaling complex with a novel lipid signaling interaction partner, and decipher the effects of loss of Nf1 on neuronal circuit excitability and function.

Public Health Relevance

Neurofibromatosis type 1 is one of the most common developmental disorders, which often affects neuropsychiatric function in afflicted individuals. This project will examine how Nf1 mutations affect behavior and neuronal circuit function in an animal model of neurofibromatosis 1. Results will provide information about potential new pathways to target for treatment of the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS097237-02S1
Application #
9635362
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Morris, Jill A
Project Start
2017-05-01
Project End
2018-07-31
Budget Start
2018-05-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458