Drosophila models of human cognitive disorders: NF1 and Noonan syndrome

描述（由申请人提供）：本提案将研究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的肿瘤毁容和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患者也有学习缺陷。NF1是由单个基因NF1突变引起的，而NS是遗传异质性的，PTPN11突变占50%。本提案将关注NF1和PTPN11在长期记忆形成中的作用。NF1编码GAP蛋白，这是Ras活性的负调节因子，而PTPN11编码一种被指定为SHP-2的蛋白，这是Ras活性的正调节因子。这两种基因在果蝇中高度保守，与人类的60%以上相同。在患者身上发现的突变也会破坏果蝇的学习和记忆能力。本研究将利用这些临床相关的突变来研究NF1及其调控的Ras活性在记忆检索中的作用，并研究PTPN11及其调控的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，即多次训练之间有休息间隔（间隔训练）产生更强的记忆。比相同次数的不间断训练（大规模训练）更持久的记忆。我希望从这项研究中产生的新见解将反过来促进这些疾病认知方面的治疗发展。这项建议包括两个具体目标，概述如下：我们将研究nf1依赖性记忆检索的神经解剖学组织和nf1调节的Ras活性在记忆检索中的作用。2. 我们将研究PTPN11及其调控的Ras/MAPK级联在确定PTPN11依赖性记忆的休息间隔长度和神经解剖组织中的作用。

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.