Drosophila models of human cognitive disorders: NF1 and Noonan syndrome

人类认知障碍的果蝇模型：NF1 和努南综合征

• 批准号: 8071505
• 负责人: YI ZHONG
• 金额: $ 34.1万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071505
• 关键词: Accounting; Affect; Child; Cognition Disorders; Cognitive; Congenital Heart Defects; Couples; Defect; Disease; Drosophila genus; Face; GTPase-Activating Proteins; Genes; Human; Impaired cognition; Investigation; Learning; Length; MAP Kinase Gene; Medical; Memory; Modeling; Molecular; Mutation; NF1 gene; Neurofibromatosis 1; Noonan Syndrome; PTPN11 gene; Pathogenesis; Pathway interactions; Patients; Peripheral Nervous System Neoplasms; Phosphoric Monoester Hydrolases; Play; Property; Protein Tyrosine Phosphatase; Proteins; Ras Signaling Pathway; Receptor Protein-Tyrosine Kinases; Regulation; Rest; Retrieval; Role; Signal Transduction Pathway; Time; Training; base; clinically relevant; gain of function mutation; gene discovery; improved; insight; long term memory; loss of function mutation; memory process; memory retrieval; public health relevance; ras GTPase-Activating Proteins; therapy development

DESCRIPTION (provided by applicant): This proposal will examine Drosophila models of human cognitive disorders, including neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). NFI is characterized by disfiguring tumors of the peripheral nervous system and learning defects in children with NFI. NS include features like distinct facial anomalies and congenital heart defects. A fraction of NS patients also have learning defects. NF1 is caused by mutations in a single gene NF1 while NS is genetically heterogeneous with mutations in PTPN11 accounting for 50%. This proposal will focus on role of NF1 and PTPN11 in long-term memory formation. NF1 encode GAP protein that is a negative regulator of Ras activity, whereas PTPN11 encodes a protein designated as SHP-2, a positive regulator of Ras activity. Both genes are highly conserved in fruit flies with more than 60% identical to humans. Mutations identified in patients also disrupt learning and memory in fruit flies. This proposal will utilize these clinically relevant mutations to study roles of NF1 and its regulated Ras activity in memory retrieval, and to study roles of PTPN11 and its regulated Ras activity in the spacing effect of long-term memory formation, which represent a universal property of memory formation as to that multiple training sessions with a rest interval between them (spaced training) produces stronger, longer-lasting memory than the same number of training sessions with no rest interval (massed training). I expect that new insights generated from this study will in turn facilitate development of treatment of the cognitive aspect of these disorders. This proposal includes two specific aims as outline below: 1. We will examine neuroanatomic organization of NF1-dependent memory retrieval and roles of NF1-regulated Ras activity in memory retrieval. 2. We will study PTPN11 and its regulated Ras/MAPK cascade in defining the length of resting intervals and neuroanatomical organization of PTPN11-dependent memory. PUBLIC HEALTH RELEVANCE: This proposal will examine Drosophila models of human cognitive disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Mutations in the NF1 and PTPN11 genes that cause NF1 and NS, respectively also disrupt memory formation in fruit flies. Study of these mutations will allow us gaining insights into molecular basis underlying memory retrieval and memory formation. Such understanding will in turn facilitate development of treatment for the disorders.

描述（由申请人提供）：该提案将检查人类认知障碍的果蝇模型，包括 1 型神经纤维瘤病 (NF1) 和努南综合征 (NS)。 NFI 的特点是周围神经系统肿瘤毁容以及 NFI 儿童的学习缺陷。 NS 包括明显的面部异常和先天性心脏缺陷等特征。一小部分 NS 患者还存在学习缺陷。 NF1是由NF1单基因突变引起的，而NS则具有遗传异质性，PTPN11突变占50%。该提案将重点关注 NF1 和 PTPN11 在长期记忆形成中的作用。 NF1 编码 GAP 蛋白，它是 Ras 活性的负调节因子，而 PTPN11 编码一种称为 SHP-2 的蛋白质，它是 Ras 活性的正调节因子。这两个基因在果蝇中高度保守，与人类的相似度超过 60%。在患者身上发现的突变也会扰乱果蝇的学习和记忆。该提案将利用这些临床相关突变来研究 NF1 及其调节的 Ras 活性在记忆检索中的作用，并研究 PTPN11 及其调节的 Ras 活性在长期记忆形成的间隔效应中的作用，这代表了记忆形成的普遍特性，即多次训练课程之间有休息间隔（间隔训练）比相同数量的无休息训练课程产生更强、更持久的记忆 间隔（集中训练）。我预计这项研究产生的新见解将反过来促进这些疾病认知方面治疗的发展。该提案包括以下两个具体目标： 1. 我们将研究 NF1 依赖性记忆检索的神经解剖结构以及 NF1 调节的 Ras 活性在记忆检索中的作用。 2. 我们将研究 PTPN11 及其调节的 Ras/MAPK 级联，以确定休息间隔的长度和 PTPN11 依赖性记忆的神经解剖结构。 公共健康相关性：该提案将研究人类认知障碍 1 型神经纤维瘤病 (NF1) 和努南综合征 (NS) 的果蝇模型。分别导致 NF1 和 NS 的 NF1 和 PTPN11 基因突变也会破坏果蝇的记忆形成。对这些突变的研究将使我们能够深入了解记忆检索和记忆形成的分子基础。这种理解反过来将促进疾病治疗的发展。