Ras/MAPK Mutations Effects on the Developing Brain

Ras/MAPK 突变对大脑发育的影响

基本信息

批准号：
10365914
负责人：
Tamar Green
金额：
$ 16.68万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365914
关键词：
11 year old Affect Age Anatomy Animal Model Astrocytes Attention Attention deficit hyperactivity disorder Axon Base of the Brain Behavior Behavior assessment Behavioral Bilateral Biological Brain Brain imaging Cardiac Child Clinical Cognition Cognitive Collection Control Groups Corpus striatum structure Costello syndrome DNA Sequence Alteration Data Development Diagnosis Diffusion Diffusion Magnetic Resonance Imaging Dimensions Disease Functional Magnetic Resonance Imaging Future Genes Genetic Genetic Diseases Genotype Growth Hippocampus (Brain)Human Hyperactive behavior Hyperactivity Image Impairment Individual Interest Group Internet Intervention Investigation Lead Learning Link MAP Kinase Gene Magnetic Resonance Imaging Measures Methods Modality Multimodal Imaging Mus Mutation Neck Neurofibromatosis 1 Neurons Noonan Syndrome Outcome Outcome Measure PTPN11 gene Parietal Pathway interactions Pharmaceutical Preparations Population Research Research Design Resolution Rest Risk Risk Behaviors Sampling Statistical Methods Structure Study models Subgroup Syndrome Testing Time Translating Turner&apos s Syndrome Variant age group base behavior measurement behavioral outcome behavioral phenotyping brain behavior cognitive control cognitive process comparison group connectome critical developmental period design executive function geometric structure girls gray matter imaging study improved inattention innovation insight mouse model myelination neural correlate neuron development novel relating to nervous system sex social deficits social skills synaptic function white matter

项目摘要

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.

抽象的 RAS/MAPK途径是大脑发育和功能的核心。在儿童中，遗传突变影响 RAS/MAPK途径导致多种疾病具有认知行为表型，统称为 “ Rasopathies”（例如Noonan综合征，神经纤维瘤病1，Costello综合征）。作为条件的集合， ras病是常见的遗传疾病（1：1,000），而Noonan综合征（NS）是最常见的这些条件（1：2,000）。 NS有强烈的经验支持影响认知和行为，特别是增加与多动症相关行为的风险，以及执行功能的损害和社交技能。此外，从NS动物模型收集的数据对脑发育显示出显着影响，大脑功能和行为。然而，面对这些值得注意的发现，没有对早期进行系统的调查迄今为止，已经进行了NS的人脑发育。这是在理解NS的主要差距增加了儿童的认知行为结果的风险。拟议的研究旨在定义NS对脑解剖结构和连通性的影响。我们的假设是，NS中的RAS/MAPK突变与注意力和注意力的神经相关性有关社交技能。我们的样本将包括40名NS在5-11岁之间的女孩，而40个性别和年龄 - 匹配通常会开发控件，并与特纳综合征的40个年龄匹配的女孩组成的（临床）组。使用高分辨率结构性MRI，扩散加权成像，静止状态fMRI和目标电池认知行为评估，我们将首先评估神经相关性和认知行为的相关性与对照相关的NS女孩的注意力和社交功能障碍相关的功能。第二，我们会的探索脑成像曲线与特定NS RAS/MAPK突变（PTPN11或SOS1）之间的关联。拟议项目的理由是，定义NS中的神经相关性将提高我们的能力了解与RAS/MAPK途径相关的神经变异如何影响注意力和认知人类的过程。关于结果，检查该人群将提供重要的见解 RAS/MAPK途径对大脑结构和连通性的影响。另外拟议的研究有望为NS的未来临床干预提供新的基于大脑的结果指标。为了例如，已经显示的RAS/MAPK途径中的药物减少激活（NS中的增强）已显示 NS小鼠模型中的学习有益影响。最后，我们的研究产生的结果将对RAS/MAPK作为一种中心生物学机制的更广泛理解显着有助于更广泛的理解为儿童的多动症和学习做出贡献。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Altered canonical and striatal-frontal resting state functional connectivity in children with pathogenic variants in the Ras/mitogen-activated protein kinase pathway.

DOI：
10.1038/s41380-021-01422-5
发表时间：
2022-03
期刊：
Molecular psychiatry
影响因子：
11
作者：
Bruno JL;Shrestha SB;Reiss AL;Saggar M;Green T
通讯作者：
Green T

Neuropsychiatric phenotypes in children with Noonan syndrome.

努南综合征儿童的神经精神表型。

DOI：
10.1111/dmcn.15627
发表时间：
2023
期刊：
Developmental medicine and child neurology
影响因子：
3.8
作者：
Naylor,PaigeE;Bruno,JenniferL;Shrestha,SharonBade;Friedman,Marcelle;Jo,Booil;Reiss,AllanL;Green,Tamar
通讯作者：
Green,Tamar

Adolescent brain development in girls with Turner syndrome.

DOI：
10.1002/hbm.26327
发表时间：
2023-07
期刊：
HUMAN BRAIN MAPPING
影响因子：
4.8
作者：
Wun, Vanessa Lozano;Foland-Ross, Lara C.;Jo, Booil;Green, Tamar;Hong, David;Ross, Judith L.;Reiss, Allan L.
通讯作者：
Reiss, Allan L.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

Ras-MAPK 致病性变异对人类大脑发育的新影响及其与基因表达和抑制能力的联系。

DOI：
10.21203/rs.3.rs-2580911/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Rai,Bhavana;Naylor,Paige;Sanchez,MonicaSiqueiros;Wintermark,Max;Raman,Mira;Jo,Booil;Reiss,Allan;Green,Tamar
通讯作者：
Green,Tamar

X-Chromosome Insufficiency Alters Receptive Fields across the Human Early Visual Cortex.

X 染色体不足会改变人类早期视觉皮层的感受野。

DOI：
10.1523/jneurosci.2745-18.2019
发表时间：
2019
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Green,Tamar;Hosseini,Hadi;Piccirilli,Aaron;Ishak,Alexandra;Grill-Spector,Kalanit;Reiss,AllanL
通讯作者：
Reiss,AllanL