Understanding intellectual disability in Noonan syndrome and related disorders

这笔赠款将主要在阿根廷#年学院生理学系进行。 布宜诺斯艾利斯大学医学院，与Mario Rafael Pagani合作(电子邮件： Pagani@fmed.uba.ar；电话和传真：54-(11)-5950-9500 x 2159)，作为NIH赠款的延伸 不是的。(5R01HL071207-08)、2002年8月1日至2013年1月31日。 我们研究的长期目标是治疗智力障碍，恢复正常学习 和行为。这个研究项目的目的是增进我们对分子的理解。 Noonan综合征(NS)的智力残疾基础。NS是一种遗传性疾病，由 编码RAS/MAPK信号成分的9个基因的功能增益突变 途径(即CBL、SHP2、SOS、RAS、RAF和MEK蛋白)。除了形态上的 异常，如心脏缺陷，智能障碍是NS和 相关疾病，也是由RAS/MAPK蛋白编码基因突变引起的 途径，证明RAS信号的增强会产生神经认知缺陷。通过 利用转NS功能增益突变的黑腹果蝇品系 PTPN11同源基因，开瓶器(CSW)，我们发现了强烈控制发育的基因 缺陷包括Ras/MAPK途径调节因子，但也包括编码Notch蛋白的缺陷 和JAK/STAT通路。此外，我们最近还展示了不同的CSW函数增益 等位基因损害了学习的一个基本属性，称为间隔效应，指的是一种 当学习课程随着时间的推移而被隔开时，你会有更持久的记忆。值得注意的是，间隔效应和 记忆缺陷可以通过药理学或行为学的方法“治愈”。在这项研究中 我们将研究RAS、Notch和JAK/STAT通路在间隔效应中的作用 以及利用果蝇模型系统所涉及的信号机制。作为一个整体， 本申请中提出的研究将描绘导致NS的基因范围 突变，并提供了对其突变蛋白产物在 生化、细胞和生物体水平。所获得的洞察力将在未来得到利用 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.