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 通路是儿童大脑发育和功能的核心，基因突变会影响儿童的大脑发育和功能。 Ras/MAPK 通路导致多种具有认知行为表型的疾病，统称为 “RASopathies”（例如 Noonan 综合征、神经纤维瘤病 1、Costello 综合征）。 RASopathies 是常见的遗传性疾病 (1:1,000)，努南综合征 (NS) 是最常见的遗传性疾病这些条件 (1:2,000) 有强有力的实证支持 NS 影响认知和行为，特别是增加与多动症相关的行为风险以及执行功能和此外，从 NS 动物模型收集的数据显示，社交技能对大脑发育有显着影响。然而，面对这些值得注意的发现，早期并没有系统的研究。迄今为止，人们对 NS 的大脑发育的研究还存在很大差距。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 对大脑解剖结构和连接性的影响。假设 NS 中的 Ras/MAPK 突变与注意力和注意力相关的神经相关性有关。我们的样本包括 40 名 5-11 岁患有 NS 的女孩，以及 40 名性别和年龄的女孩。与正常发育的对照组和由 40 名年龄匹配的患有特纳综合征的女孩组成的（临床）组相匹配。使用高分辨率结构 MRI、扩散加权成像、静息态 fMRI 和一组目标认知行为评估，我们将首先评估认知行为的神经相关性与对照相比，NS 女孩的注意力和社交功能障碍具有相关特征。探索脑成像特征与特定 NS Ras/MAPK 突变（PTPN11 或 SOS1）之间的关联。该项目的基本原理是定义 NS 中的神经相关性将提高我们的能力了解与 Ras/MAPK 通路相关的神经变化如何影响注意力和认知就结果而言，研究这个群体将为我们提供重要的见解。除了拟议的研究之外，Ras/MAPK 通路对大脑结构和连接的影响。有望为 NS 的未来临床干预提供新颖的基于大脑的结果测量。例如，减少 Ras/MAPK 通路激活（在 NS 中增强）的药物已经显示对 NS 小鼠模型学习的有益影响最后，我们的研究得出的结果将是。极大地促进了对 Ras/MAPK 作为核心生物机制的更广泛理解有助于儿童多动症和学习。

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