Neurobiology and Treatment of Reading Disability in NF1
神经生物学和 NF1 阅读障碍的治疗
基本信息
- 批准号:10628742
- 负责人:
- 金额:$ 25.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcademyAmericanAnimalsBehavioralBehavioral MechanismsChildClinicalClinical TrialsCognitionCognitiveCognitive deficitsGeneral PopulationGenetic DiseasesGoalsHumanImpairmentIncidenceInterventionLearningLearning DisabilitiesLinkLong-Term PotentiationLovastatinMeasuresMemoryMusMutationNF1 geneNeurobiologyNeurocutaneous SyndromesNeurofibromatosis 1OxidoreductaseParentsPediatricsPharmaceutical PreparationsPharmacologic SubstancePharmacological TreatmentPhaseProteinsReadingReading DisabilitiesResearchResearch DesignResearch PersonnelRiskSchool-Age PopulationSignal PathwaySignal TransductionSumTimeTrainingTranslational ResearchWorkbasebehavioral pharmacologydevelopmental diseaseinhibitormouse modelneuromechanismphonologyreading difficultiesskillstutoring
项目摘要
PROJECT SUMMARY/ABSTRACT
Neurofibromatosis Type 1 (NF1), an autosomal dominant neurocutaneous syndrome with an incidence of
1:3000, is caused by a mutation in neurofibromin -- a protein that negatively impacts learning by altering RAS
signaling in long term potentiation (LTP). Clinically, NF1 shows four times greater rate of learning disabilities
(65%) compared to the general population (15%), including reading disability (RD), resulting in educational
impairment. The negative impact on academics makes these learning disabilities, including reading disability,
among the most common concerns of parents of children with NF1. In previous research (NS49096), we
demonstrated that children with NF-1 with reading difficulty (NF+RD) are able to respond to standard
phonologically-based reading tutoring that was originally developed to treat children in the general population
with idiopathic reading disability (IRD). Of central importance to this application, another line of research in the
mouse model of NF has shown that pharmacological treatment (Lovastatin) reverses learning deficits (Li et al.,
2005). The assumed mechanism is that Lovastatin, an HMGCoA reductase inhibitor, upregulates RAS
signaling to counteract the negative LTP effects of deficient neurofibromin, thus allowing for better memory
formation during learning. This finding has stimulated translational research to assess whether Lovastatin, a
medication that the American Academy of Pediatrics to endorses as safe to use in children, can reverse
cognitive deficits in humans with NF1. Promising results have been found in studies that, similar to the mouse
studies, measure specific cognitive domains or pair Lovastatin with training of the deficient skill. Given that (a)
NF+RD benefit from reading tutoring and (b) pharmaceutical benefits appear linked to specific study designs,
several next steps are needed to better understand the behavioral and neural mechanisms of cognition in NF1.
Specifically, we propose a clinical trial in which we pre-treat the NF+RD children with Lovastatin for the 12
weeks prior to reading tutoring, as compared to NF+RD who receive either reading tutoring or Lovastatin;
critically, like animal studies, we will target those who show impaired learning on the specific skill to be taught,
i.e., NF+RD will receive reading tutoring. Both behavioral and neurobiological measures are proposed, and
changes in functional and structural connectivity are expected to occur with enhanced cognition. In particular,
the combination of behavioral and pharmacological intervention is hypothesized to have a synergistic effect
producing greater gains in cognition and changes in neurobiology than Lovastatin or tutoring alone. In sum,
our overarching goal in this next phase of our research is to capitalize on current findings to elucidate
mechanisms of and best treatments for the cognitive deficits in NF1. Such approach could also have a
broader applicability for better understanding human learning mechanisms in developmental disorders.
项目总结/摘要
1型神经纤维瘤病(NF 1)是一种常染色体显性遗传的神经皮肤综合征,
1:3000,是由神经纤维蛋白的突变引起的-一种通过改变RAS对学习产生负面影响的蛋白质
长时程增强(LTP)在临床上,NF 1表现出四倍的学习障碍率
(65与一般人群(15%)相比,包括阅读残疾(RD),
损伤对学业的负面影响使得这些学习障碍,包括阅读障碍,
这是NF 1患儿父母最关心的问题之一。在先前的研究(NS 49096)中,我们
证明NF-1伴阅读困难(NF+RD)的儿童能够对标准的
一种以语音为基础的阅读辅导,最初是为治疗普通人群中的儿童而开发的
患有特发性阅读障碍(IRD)。对这一应用至关重要的是,
NF的小鼠模型显示药物治疗(洛伐他汀)逆转学习缺陷(Li等,
2005年)。推测其机制是HMGCoA还原酶抑制剂洛伐他汀上调RAS
信号传导以抵消缺乏神经纤维蛋白的负LTP效应,从而允许更好的记忆
在学习过程中形成。这一发现刺激了转化研究,以评估是否洛伐他汀,
美国儿科学会认可的儿童安全用药,
NF 1患者的认知缺陷。在研究中发现了有希望的结果,类似于小鼠
研究,测量特定的认知领域或将洛伐他汀与缺乏技能的训练配对。鉴于(a)
NF+RD受益于阅读辅导和(B)药物益处似乎与特定研究设计相关,
接下来的几个步骤需要更好地理解NF 1中认知的行为和神经机制。
具体来说,我们提出了一项临床试验,在该试验中,我们对12名NF+RD儿童进行了洛伐他汀预治疗,
与接受阅读辅导或洛伐他汀的NF+RD组相比,阅读辅导前6周;
关键的是,像动物研究一样,我们将针对那些在要教授的特定技能上表现出学习障碍的人,
也就是说,NF+RD将接受阅读辅导。提出了行为和神经生物学措施,
随着认知能力的增强,预期功能和结构连接性会发生变化。特别是,
行为和药物干预的组合被假设具有协同效应
在认知和神经生物学方面的变化比单独使用洛伐他汀或辅导更大。总的来说,
我们在下一阶段研究的首要目标是利用目前的发现来阐明
NF 1认知缺陷的机制和最佳治疗方法。这种方法也可以有一个
更广泛的适用性,以更好地了解人类学习机制的发展障碍。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Commentary: Dimensionality in environmental adversity, mechanisms of emotional socialization, and children's characteristics and cognitive growth - a reflection on Miller et al. (2020).
评论:环境逆境中的维度、情感社会化机制以及儿童的特征和认知成长——对米勒等人的反思。
- DOI:10.1111/jcpp.13293
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Nguyen,TinQ;Cutting,LaurieE
- 通讯作者:Cutting,LaurieE
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Laurie E Cutting其他文献
Laurie E Cutting的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Laurie E Cutting', 18)}}的其他基金
Neural Correlates of Discourse Processing in Adolescents
青少年话语处理的神经相关性
- 批准号:
10687822 - 财政年份:2022
- 资助金额:
$ 25.51万 - 项目类别:
6/6 HBCD Prenatal Experiences and Longitudinal Development (PRELUDE) Consortium Vanderbilt
6/6 六溴环十二烷产前经历和纵向发展 (PRELUDE) 联盟范德比尔特
- 批准号:
10494153 - 财政年份:2021
- 资助金额:
$ 25.51万 - 项目类别:
6/6 HBCD Prenatal Experiences and Longitudinal Development (PRELUDE) Consortium Vanderbilt
6/6 六溴环十二烷产前经历和纵向发展 (PRELUDE) 联盟范德比尔特
- 批准号:
10661775 - 财政年份:2021
- 资助金额:
$ 25.51万 - 项目类别:
Early Academic Achievement and Intervention Response: Role of Executive Function
早期学业成就和干预反应:执行功能的作用
- 批准号:
10329261 - 财政年份:2021
- 资助金额:
$ 25.51万 - 项目类别:
6/6 HBCD Prenatal Experiences and Longitudinal Development (PRELUDE) Consortium Vanderbilt
6/6 六溴环十二烷产前经历和纵向发展 (PRELUDE) 联盟范德比尔特
- 批准号:
10380490 - 财政年份:2021
- 资助金额:
$ 25.51万 - 项目类别:
6/6 HBCD Prenatal Experiences and Longitudinal Development (PRELUDE) Consortium Vanderbilt
6/6 六溴环十二烷产前经历和纵向发展 (PRELUDE) 联盟范德比尔特
- 批准号:
10748148 - 财政年份:2021
- 资助金额:
$ 25.51万 - 项目类别:
相似海外基金
Collaborative Research: REU Site: Earth and Planetary Science and Astrophysics REU at the American Museum of Natural History in Collaboration with the City University of New York
合作研究:REU 地点:地球与行星科学和天体物理学 REU 与纽约市立大学合作,位于美国自然历史博物馆
- 批准号:
2348998 - 财政年份:2025
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
Collaborative Research: REU Site: Earth and Planetary Science and Astrophysics REU at the American Museum of Natural History in Collaboration with the City University of New York
合作研究:REU 地点:地球与行星科学和天体物理学 REU 与纽约市立大学合作,位于美国自然历史博物馆
- 批准号:
2348999 - 财政年份:2025
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
Understanding Latin American Challenges in the 21st Century (LAC-EU)
了解拉丁美洲在 21 世纪面临的挑战 (LAC-EU)
- 批准号:
EP/Y034694/1 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Research Grant
Conference: North American High Order Methods Con (NAHOMCon)
会议:北美高阶方法大会 (NAHOMCon)
- 批准号:
2333724 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
Collaborative Research: RUI: Continental-Scale Study of Jura-Cretaceous Basins and Melanges along the Backbone of the North American Cordillera-A Test of Mesozoic Subduction Models
合作研究:RUI:北美科迪勒拉山脊沿线汝拉-白垩纪盆地和混杂岩的大陆尺度研究——中生代俯冲模型的检验
- 批准号:
2346565 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
REU Site: Research Experiences for American Leadership of Industry with Zero Emissions by 2050 (REALIZE-2050)
REU 网站:2050 年美国零排放工业领先地位的研究经验 (REALIZE-2050)
- 批准号:
2349580 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
Collaborative Research: RUI: Continental-Scale Study of Jura-Cretaceous Basins and Melanges along the Backbone of the North American Cordillera-A Test of Mesozoic Subduction Models
合作研究:RUI:北美科迪勒拉山脊沿线汝拉-白垩纪盆地和混杂岩的大陆尺度研究——中生代俯冲模型的检验
- 批准号:
2346564 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
Conference: Latin American School of Algebraic Geometry
会议:拉丁美洲代数几何学院
- 批准号:
2401164 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
Collaborative Research: Ionospheric Density Response to American Solar Eclipses Using Coordinated Radio Observations with Modeling Support
合作研究:利用协调射电观测和建模支持对美国日食的电离层密度响应
- 批准号:
2412294 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant
Conference: Doctoral Consortium at Student Research Workshop at the Annual Conference of the North American Chapter of the Association for Computational Linguistics (NAACL)
会议:计算语言学协会 (NAACL) 北美分会年会学生研究研讨会上的博士联盟
- 批准号:
2415059 - 财政年份:2024
- 资助金额:
$ 25.51万 - 项目类别:
Standard Grant