Understanding intellectual disability in Noonan syndrome and related disorders

描述(由申请人提供)：这笔赠款将主要在阿根廷布宜诺斯艾利斯大学医学院生理系与马里奥·拉斐尔·帕加尼(电子邮件：pagani@fmed.uba.ar；电话和传真：54-(11)-5950-9500 x 2159)合作进行，作为NIH补助金编号的延伸。(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，恢复正常的学习和行为。本研究的目的是促进我们对Noonan综合征(NS)智力障碍的分子基础的理解。NS是一种遗传性疾病，由9个编码RAS/MAPK信号通路组成部分(即CBL、SHP2、SOS、RAS、RAF和MEK蛋白)的基因功能获得突变引起。除了心脏缺陷等形态异常外，智能障碍也是NS和相关疾病的共同特征，也是由RAS/MAPK途径中编码蛋白质的基因突变引起的，这证明RAS信号的增强会产生神经认知障碍。通过使用在果蝇PTPN11同源基因中存在NS功能增益突变的转基因黑腹果蝇，我们发现了强烈控制发育缺陷的基因，包括Ras/MAPK途径调节因子，以及编码Notch和JAK/STAT途径蛋白的基因。此外，我们最近发现，不同的CSW功能增益等位基因会损害学习的一种基本属性，即间隔效应，即当学习过程随着时间的推移而间隔时，会产生更持久的记忆。值得注意的是，间隔效应和记忆缺陷是可以通过药物或行为方法“治愈”的。在这项研究中，我们将通过一个果蝇模型系统来研究RAS、Notch和JAK/STAT通路在间隔效应中的作用和涉及的信号机制。作为一个整体，本申请中提出的研究将描绘在突变时导致NS的基因范围，并提供对其突变蛋白产物在生化、细胞和生物水平上的影响的见解。所获得的见解将在未来被用来阐明认知缺陷的遗传原因，以及开发新的治疗策略来改善这些表型。 公共卫生相关性：更好地了解Noonan综合征和相关疾病导致智力残疾的分子机制将导致潜在的药物或行为疗法。我们目前对Noonan综合征及相关疾病的了解仅限于与Ras/MAPK信号通路改变相关的机制，仅有少数涉及的主要基因的机制与智能障碍有关。表征与Noonan综合征改变相关的其他基因的作用，RAS，Notch和STAT，将为科学研究以及治疗干预提供额外的靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: A better understanding the molecular mechanisms underlying intellectual disability in Noonan syndrome and related disorders will lead to potential pharmacological or behavioral therapies. Our current understanding about Noonan syndrome and related disorders is limited to mechanisms related with the alteration of Ras/MAPK signaling pathway and only a few mechanisms about the principal genes involved are known for intellectual disability. Characterizing the role of other genes associated with Noonan syndrome alteration, RAS, Notch and STAT, will provide additional targets for scientific studies as wel as for therapeutic intervention.