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Tomchik Lab Awarded New NIH R01 Grant to Study How Nf1 Modulates Metabolism

February 24, 2022


Neurofibromatosis type 1 causes tumors, cognitive/behavioral symptoms, and alters metabolism. A new grant from NIH/NINDS will fund research into how mutations in the underlying gene/protein, Nf1, modulate metabolic rate, which could influence disease pathophysiology.









Genetic neurodevelopmental disorders clearly affect the brain and nervous system, as well as affecting other bodily functions. For instance, the genetic disorder neurofibromatosis type 1 (NF1) causes tumors and alters susceptibility for cognitive and behavioral disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Recent evidence also suggests that it affects metabolism, which could feed back into the other symptoms.


How do the genetic mutations that cause NF1 alter metabolism? Do the NF1 metabolic effects contribute to the other symptoms of the disorder?

A new research grant (R01) awarded by the National Institute of Neurological Disorders and Stroke, of the U.S. National Institutes of Health, will fund a 5-year study in the Tomchik lab to dissect the mechanisms of NF1 effects on metabolism.


NF1 is caused by mutations in a gene that encodes a protein called neurofibromin. This protein is a tumor suppressor, and when it is lost, individuals are predisposed to a range of benign tumors and cancers. In addition, neurofibromin plays a signaling role in multiple cell types throughout the body, including the neurons in the brain. Loss of neurofibromin alters neuronal function - in relatively subtle ways - increasing the risk for ADHD and ASD (among other comorbidities).


Emerging evidence suggests that NF1 may affect metabolism in humans and animal models. If so, the metabolic effects could contribute to the disease symptoms, and may represent a novel treatment strategy in the future. To investigate the NF1 link to metabolism, we are examining whether neurofibromin modulates metabolism in the fruit fly, Drosophila melanogaster, which shares fundamental features of neuronal function and metabolism with other animals (including humans). Preliminary studies revealed that neurofibromin mutations increase metabolic rate, alter fat stores and turnover, and increase feeding. These effects are due specifically to neurofibromin actions in a set of neurons in the nervous system, acting through a particular signaling pathway (Ras/MAPK).


Following up on our preliminary observations, this new grant will dissect the mechanisms of NF1 metabolic effects, laying the groundwork for potential downstream development of novel therapeutic strategies to treat NF1. We thank the NIH/NINDS for the support of this research.





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