Mechanisms of Nf1 Pathophysiology Underlying Hyperactivity

项目摘要 1型神经纤维瘤病是最常见的单基因发育障碍之一，影响~1 全球有3500人。某种形式的认知或神经精神障碍出现在 大约50%-80%的人患有NF1，这些被认为是终生的主要原因 发病率。神经纤维素蛋白(NF1)直接抑制RAS信号，但也影响其他几个信号 信令级联(可能是间接的)。所涉及的信令级联的复杂性 神经纤维瘤病1，再加上缺乏直接靶向NF1的药物，突出了对 针对NF1表型的新方法。神经纤维瘤病1相关基因修饰因子的发现 细胞功能障碍将为治疗这种疾病提供潜在的新靶点。 这个项目将集中在果蝇失去功能的Nf1突变体中的多动和重复行为。这个 这些行为缺陷的大效应规模将使他们能够将其用作读数来解开体内的 神经纤维蛋白在强大的遗传模式生物中的分子和电路功能。特定的 AIMS将研究NF1缺乏症多动的电路机制，剖析分子 NF1调节多动的机制，并发现新基因在发育中的作用 NF1表型。

Project Summary 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 considered to be 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 modifiers 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 the circuit mechanisms underlying hyperactivity in NF1 deficiency, dissect the molecular mechanisms of Nf1-regulated hyperactivity, and discover the roles of novel genes underlying the development of NF1 phenotypes.