权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of Nf1 pathophysiology underlying hyperactivity

多动症背后的 Nf1 病理生理学机制

基本信息

批准号：
9912875
负责人：
Seth M Tomchik
金额：
$ 51.83万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912875
关键词：
Affect Anatomy Animal Model Attention deficit hyperactivity disorder Behavior Behavioral Behavioral Genetics Cognitive Complex Cyclic AMP Data Defect Development Disease Drosophila genus Exhibits Functional disorder Genetic Genetic Models Grooming Human Hyperactive behavior Image Individual Lipids Mediating Molecular Morbidity - disease rate Motor Activity Mutate Mutation NF1 gene NF1 mutation Neurofibromatosis 1 Neuronal Dysfunction Neurons Outcome Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Physiology Point Mutation Protein Isoforms Proteins Publishing RNA Splicing Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Sleep Sleep Deprivation Stereotyped Behavior Study models Symptoms Testing Time Transgenic Organisms behavior test behavioral phenotyping comorbidity developmental disease experimental study fly genetic manipulation human disease in vivo in vivo evaluation in vivo imaging insight knock-down loss of function mutant neural circuit neuronal circuitry neuropsychiatric disorder neuropsychiatry neurotransmission novel novel strategies optogenetics protein function ras GTPase-Activating Proteins relating to nervous system repetitive behavior

项目摘要

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.

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。