PROJECT SUMMARY/ABSTRACT
Neurofibromatosis type 1 is a common monogenic developmental disorder, affecting 1 in 3,000 individuals
worldwide. Neurofibromatosis type 1 is a progressive developmental disorder caused by mutations in
the NF1 gene, which encodes for the protein neurofibromin (Nf1). Neurofibromatosis type 1 patients are
predisposed to developing a range of complications, including peripheral nerve associated neurofibromas,
malignant tumors, skeletal abnormalities, reduced overall growth, and neurocognitive deficits. These
complications significantly affect patients’ quality of life and contribute to the overall decreased life expectancy
of those with the disease. Emerging studies suggest that mutations in NF1 may alter metabolism;
neurofibromatosis type 1 patients exhibit multisystemic symptoms and abnormalities such as short stature,
pituitary growth hormone deficiencies, and reduced body mass indexes. However, the mechanism by which Nf1
modulates metabolism is unknown. My recently published data suggest that Nf1 regulates metabolism via a
discrete neuronal circuit, creating the opportunity to study the mechanisms of Nf1-mediated neuronal control of
metabolism. Here, I propose to elucidate the mechanisms by which Nf1 regulates neuronal activity, leading to
metabolic dysregulation and contributing to neurofibromatosis type 1 disease pathophysiology when mutated.
Experiments will leverage the well-established Drosophila model of neurofibromatosis type 1, its highly
conserved signaling pathways, and the organism’s experimental and genetic power to study the novel
interactions between Nf1, neuronal circuit activity, and metabolism. This research will identify the key signaling
pathway activated by Nf1 to regulate metabolism within neurons (Aim 1) and test the effects of Nf1 on neuronal
and circuit physiology, leading to metabolic dysregulation (Aim 2). This will be achieved using a comprehensive
and powerful combination of genetics, neural circuit analysis, and novel functional in vivo imaging. In sum, the
proposed research is among the first studies to use optical imaging to study a central neuronal circuit that has
been shown to regulate metabolism and provide a detailed dissection of the neural circuits mediating Nf1
metabolic effects. Importantly, discerning the effect of Nf1 on metabolic rate will be essential in understanding
the multisystemic symptoms of neurofibromatosis type 1, particularly those controlled by the central nervous
system, and provide critical information on the link between Nf1 and metabolism.