Mechanisms of Nf1 pathophysiology underlying hyperactivity

1型神经纤维瘤病是最常见的单基因发育障碍之一， 全球3,500人。某些形式的认知或神经精神功能障碍存在于 大约50-80%的人患有NF 1，这些通常被认为是终身的主要原因 发病率神经纤维素蛋白（Nf 1）直接抑制Ras信号传导，但也影响其他几种蛋白质。 信号级联（可能是间接的）。信号级联的复杂性与 神经纤维瘤病1，加上缺乏直接靶向Nf 1的药物，突出了对Nf 1的迫切需要。 针对NF 1表型的新方法。揭示神经纤维瘤病1相关的遗传修饰 细胞功能障碍将为治疗这种疾病提供潜在的新靶点。 该项目将集中在果蝇功能丧失nf 1突变体的多动和重复行为。的 这些行为缺陷的大效应量将使它们能够将其用作读出，以解开体内 神经纤维蛋白在一个强大的遗传模型生物体中的分子和电路功能。具体 目的是研究Nf 1功能丧失如何影响多动/重复行为，测试信号传导， Nf 1功能背后的遗传相互作用，探索其在一种新型脂质的假定信号复合物中的作用 信号相互作用伙伴，并破译Nf 1的损失对神经元回路兴奋性和功能的影响。

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.