Mechanisms of Nf1 Pathophysiology Underlying Hyperactivity

多动症背后的 Nf1 病理生理学机制

• 批准号: 10721723
• 负责人: Seth M Tomchik
• 金额: $ 10.41万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-11 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10721723
• 关键词: Mechanisms; Nf1; Pathophysiology; Underlying; Hyperactivity

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.

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3500个人。某种形式的认知或神经精神诊断功能障碍存在于 大约50-80％的NF1个体，这些人被认为是终生的主要原因 发病率。神经纤维蛋白蛋白（NF1）直接抑制RAS信号，但也影响了其他几个 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，与缺乏直接靶向NF1的药物相结合，突出了对的紧迫需求 靶向NF1表型的新方法。发现神经纤维瘤病的遗传修饰符1相关 细胞功能障碍将为治疗这种疾病提供潜在的新靶标。 该项目将集中于果蝇丧失功能NF1突变体的多动症和重复行为。这 这些行为缺陷的巨大效果大小将使它们用作读数，以解开体内 在强大的遗传模型生物中，神经纤维蛋白蛋白的分子和电路功能。具体的 AIMS将研究NF1缺乏症中过度活跃的电路机制，剖析分子 NF1调节的多动症的机制，并发现发育发展的新基因的作用 NF1表型。