Ras/MAPK Mutations Effects on the Developing Brain

摘要 Ras/MAPK通路是大脑发育和功能的中心。在儿童中，基因突变影响 Ras/MAPK途径导致具有认知行为表型多种疾病，统称为 “RASopathies”（例如努南综合征、神经纤维瘤病1、Costello综合征）。作为条件的集合， RASopathies是常见的遗传性疾病（1：1，000），努南综合征（NS）是最常见的 这些条件（1：2,000）。有强有力的经验支持，NS影响认知和行为， 特别是增加与ADHD相关的行为风险，以及执行功能障碍， 社交能力此外，从NS动物模型收集的数据显示对脑发育的显著影响， 大脑功能和行为。然而，面对这些值得注意的发现，没有系统的研究， 迄今为止，已经在NS中进行了人脑发育。因此，在理解NS如何 增加儿童认知行为结果不佳的风险。 拟议的研究旨在确定NS对大脑解剖和连接的影响。我们 假设NS中Ras/MAPK突变与涉及注意力的神经相关物相关， 社交能力我们的样本将包括40名5-11岁的NS女孩，与40名性别和年龄- 与发育正常的对照组和40名年龄匹配的特纳综合征女孩（临床）组相匹配。 使用高分辨率结构磁共振成像，弥散加权成像，静息状态功能磁共振成像，和一组有针对性的 认知行为评估，我们将首先评估神经相关的，和认知行为 与对照组相比，NS女孩的注意力和社会功能障碍特征。二是 探索脑成像图谱与特定NS Ras/MAPK突变（PTPN 11或SOS 1）之间的关联。 该项目的基本原理是，在NS中定义神经相关物将提高我们的能力， 了解与Ras/MAPK通路相关的神经变异如何影响注意力和认知能力， 人类的过程。关于结果，研究这一人群将提供重要的见解， Ras/MAPK通路对大脑结构和连接的影响。此外，拟议的研究 有望为NS的未来临床干预提供新的基于脑的结局指标。为 例如，药物降低Ras/MAPK通路的激活（在NS中增强）已经表明， 在NS小鼠模型中对学习的有益作用。最后，我们的研究结果将 显著有助于更广泛地理解Ras/MAPK作为一种重要的生物学机制 导致儿童多动症和学习障碍。

Abstract The Ras/MAPK pathway is central for brain development and function. In children, genetic mutations affecting the Ras/MAPK pathway lead to multiple disorders with cognitive-behavioral phenotypes, collectively termed “RASopathies” (e.g. Noonan syndrome, neurofibromatosis 1, Costello syndrome). As a collection of conditions, RASopathies are common genetic disorders (1:1,000), and Noonan syndrome (NS) is the most common of these conditions (1:2,000). There is strong empirical support that NS affects cognition and behavior, particularly increasing risk for behaviors associated with ADHD, and impairments in executive function and social skills. Further, data collected from animal models of NS show significant effects on brain development, brain function and behavior. Yet, in the face of these notable findings, no systematic investigation of early human brain development in NS has been conducted to date. Thus, major gaps exist in understanding how NS increases risk for suboptimal cognitive-behavioral outcome in children. The proposed research is designed to define the effects of NS on brain anatomy and connectivity. Our hypothesis is that Ras/MAPK mutations in NS are associated with neural correlates implicated in attention and social skills. Our sample will include 40 girls with NS seen at 5-11 years of age compared to 40 sex- and age- matched typically developing controls and to a (clinical) group of 40 age-matched girls with Turner syndrome. Using high-resolution structural MRI, diffusion-weighted imaging, resting state fMRI, and a targeted battery of cognitive-behavioral assessments, we will first assess the neural correlates of, and cognitive-behavioral features associated with attentional and social dysfunction in girls with NS relative to controls. Second, we will explore associations between brain imaging profiles and specific NS Ras/MAPK mutations (PTPN11 or SOS1). The rationale for the proposed project is that defining the neural correlates in NS will improve our ability to understand how neural variations associated with the Ras/MAPK pathway affect attention and cognitive processes in humans. With respect to outcome, examining this population will provide important insights into the effects of the Ras/MAPK pathway on brain structure and connectivity. In addition the proposed research holds promise for providing novel brain-based outcome measures for future clinical interventions in NS. For example, medication decreasing activation in the Ras/MAPK pathway (enhanced in NS) already has showed beneficial effects on learning in mouse models of NS. Finally, the results generated from our study will significantly contribute to a broader understanding of the Ras/MAPK as a central biological mechanism contributing to ADHD and learning in children.