Understanding intellectual disability in Noonan syndrome and related disorders

该补助金将主要在阿根廷的生理学系， 医学，布宜诺斯艾利斯大学与Mario Rafael帕加尼合作（电子邮件： pagani@fmed.uba.ar;电话和传真：54-（11）-5950-9500 x 2159），作为NIH资助的延伸 号（5 R 01 HL 071207 -08），2002年1月8日至2013年1月31日。 我们研究的长期目标是治疗智力残疾和恢复正常学习 和行为。这项研究项目的目的是促进我们对分子生物学的理解。 努南综合征（NS）智力障碍的基础。NS是一种遗传性疾病， 编码Ras/MAPK信号传导组分的9个基因中的功能获得性突变 途径（即，CBL、SHP 2、SOS、RAS、RAF和MEK蛋白）。除了形态学 异常，如心脏缺陷，智力残疾是NS的常见特征， 相关疾病，也是由Ras/MAPK蛋白编码基因突变引起的 通路，证明RAS信号的增强产生神经认知缺陷。通过 使用在果蝇中具有NS功能获得性突变的转基因果蝇品系， PTPN 11直系同源物，螺旋形（csw），我们确定了基因，强烈控制发育 缺陷包括Ras/MAPK通路调节物，但也包括编码Notch蛋白的缺陷 JAK/STAT信号通路。此外，我们最近发现，不同的csw获得功能， 等位基因损害了学习的一个基本特性，称为间隔效应，这是指 当学习时间间隔较长时，记忆力更持久。值得注意的是，间距效应和 记忆缺陷可以通过药物或行为方法“治愈”。本研究 本项目将研究RAS、Notch和JAK/STAT通路在间隔效应中的作用 以及使用果蝇模型系统所涉及的信号机制。整体来看， 在本申请中提出的研究将描绘引起NS的基因的范围， 突变，并提供洞察其突变蛋白质产品的影响， 生物化学、细胞和有机体水平。所获得的见解将在未来得到利用 阐明认知缺陷的遗传原因以及开发新的治疗方法， 改善这些表型的策略。

This grant will be performed primarily in Argentina at the Department of Physiology, School of Medicine, University of Buenos Aires in collaboration with Mario Rafael Pagani (email: pagani@fmed.uba.ar; phone and fax: 54-(11)-5950-9500 x 2159), as an extension of NIH Grant No. (5R01HL071207-08), 08/01/2002 to 01/31/2013. The long-term goal of our research is to treat intellectual disability and restore normal learning and behavior. The aim of this research project is to advance our understanding of the molecular basis of the intellectual disability in Noonan syndrome (NS). NS is a genetic disorder caused by gain-of-function mutations in nine genes encoding components of the Ras/MAPK signaling pathway (i.e., CBL, SHP2, SOS, RAS, RAF and MEK proteins). In addition to morphological abnormalities such as cardiac defects, intellectual disability is a common feature in NS and related disorders, also caused by mutations in genes encoding proteins in the Ras/MAPK pathway, documenting that enhancement of RAS signaling produces neurocognitive defects. By using transgenic Drosophila melanogaster lines with NS gain-of-function mutations in the fly PTPN11 orthologue, corkscrew (csw), we identified genes that strongly control developmental defects including Ras/MAPK pathway regulators but also ones encoding proteins of the Notch and JAK/STAT pathway. In addition, we recently showed that different csw gain-of-function alleles impair a fundamental property of learning called the spacing effect, which refers to a longer-lasting memory when study session is spaced over time. Of note, the spacing effect and memory deficit was "curable" by a pharmacological or behavioral approach. In this research project we will examine the role of RAS, Notch and JAK/STAT pathways in the spacing effect and the signaling mechanisms involved by using a Drosophila model system. Taken as a whole, the studies proposed in this application will delineate the range of genes that cause NS when mutated as well as provide insights into the effects of their mutant protein products at the biochemical, cellular, and organismal levels. The insights gained will be leveraged in the future to elucidate genetic causes of cognitive defects as wel as to develop novel therapeutic strategies to ameliorate these phenotypes.