Structure and Function of Neonatal Social Communication in Genetic Mouse Models of Autism
自闭症遗传小鼠模型中新生儿社交沟通的结构和功能
基本信息
- 批准号:10005276
- 负责人:
- 金额:$ 34.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-21 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:22q11.2AddressAdultAge-MonthsAttenuatedBehaviorBehavioralBrainCaringChromosomal DuplicationCopy Number PolymorphismCopying ProcessesEarly InterventionEnvironmental Risk FactorEpigenetic ProcessExhibitsGene ExpressionGene Expression RegulationGenesGeneticGenetic DiseasesGenetic RiskGoalsHousingHumanIndividualMeasuresMethodsMethylationModelingModificationMothersMusNeonatalOutcomePositioning AttributeRisk FactorsRoleSeveritiesStructureSymptomsTestingTherapeutic InterventionWorkautism spectrum disorderbasebehavioral phenotypingearly experiencegene environment interactiongenetic risk factorgenetic variantimprovedinnovationmaternal separationmouse modelneonatal periodneonatenovelpupsocial communicationsynergismtoolvocalization
项目摘要
A critical step to improving our understanding of autism spectrum disorder (ASD) is to identify underlying
genetic and environmental risk factors. A number of rare copy number variants (CNVs) have emerged as
robust genetic risk factors for ASD. However, not all individuals exhibit ASD and the severity of ASD symptoms
varies among carriers of a CNV. Given that early therapeutic intervention attenuates symptoms, it is
reasonable to assume that early environmental factors also influence ASD symptoms later. However,
manipulation of the interplay between genetic and early environmental factors to identify mechanisms is
difficult in humans. Our team is uniquely positioned to experimentally address this issue. First, we have
identified atypical pup vocal call sequences of a genetic mouse model of ASD. To do so, our team applied a
set of sophisticated statistical tools. Second, our team developed innovative experimental tools and
demonstrated that such atypical pup call sequences induce less maternal approach. This observation shows
that neonatal vocalization is a means of social communication with mothers and suggests that it influences the
level of maternal care. Third, we found that enriched housing, an environmental manipulation known to reverse
the detrimental behavioral effects of maternal separation in mice, alters the expression and methylation of a
CNV-encoded gene in mouse brains. Capitalizing on these innovative methods and observations, we propose
to test our central hypothesis that CNVs disturb neonatal social communication with the mother and
this early experience exacerbates ASD-like behaviors via epigenetically modified expression of CNV-
encoded genes. We will use mouse models of paternal 15q11-13 duplication, 15q13.3 hemizygosity and
22q11.2 hemizygosity, as they represent three robust genetic risk factors for ASD. Use of multiple models will
allow us to determine common, as well as distinct roles of neonatal social communication in CNV-associated
ASD. We propose to achieve the following three Aims: Aim 1: Determine if CNVs result in atypical vocalization
structure during the neonatal period and if it is correlated with ASD-like behaviors at 2 months of age; Aim 2:
Determine the impact of atypical neonatal vocalization on maternal care; Aim 3: Measure the effect of altered
maternal care on the severity of ASD-like behaviors and CNV gene expression and epigenetic modification.
The outcomes of this project will reveal the interplay between genetic factors and neonatal social
communication with mothers resulting in the ultimate severity of ASD-like behaviors through epigenetic
mechanisms. The project has high translational value because it could provide a novel mechanistic base to
understand the gene-environment interaction underlying ASD.
提高我们对自闭症谱系障碍(ASD)的理解的关键一步是确定潜在的
遗传和环境风险因素。一些罕见的拷贝数变异(CNVs)已经出现,
ASD的强大遗传风险因素。然而,并非所有个体都表现出ASD和ASD症状的严重程度
不同的CNV携带者。考虑到早期治疗干预可以减轻症状,
早期的环境因素也会影响以后的ASD症状。然而,在这方面,
操纵遗传和早期环境因素之间的相互作用,以确定机制,
在人类中很难。我们的团队处于独特的位置,可以通过实验解决这个问题。首先我们得
鉴定了ASD遗传小鼠模型的非典型幼鼠声音呼叫序列。为此,我们的团队应用了
一套复杂的统计工具。其次,我们的团队开发了创新的实验工具,
证明了这种非典型的幼崽叫声序列诱导较少的母性接近。这一观察表明,
新生儿发声是与母亲进行社会交流的一种手段,并表明它会影响新生儿的
产妇护理水平。第三,我们发现,丰富的住房,一个环境操纵已知扭转
母亲分离对小鼠有害的行为影响,改变了一种基因的表达和甲基化,
小鼠大脑中的CNV编码基因。利用这些创新的方法和观察,我们建议
为了验证我们的核心假设,即CNV干扰了新生儿与母亲的社会交流,
这种早期经历通过CNV的表观遗传修饰表达加剧了ASD样行为,
编码基因我们将使用父系15 q11 -13重复、15q13.3半合子和
22q11.2半合子,因为它们代表了ASD的三个强大的遗传风险因素。使用多个模型将
使我们能够确定共同的,以及不同的作用,新生儿的社会沟通,在CNV相关的
自闭症我们提出了以下三个目标:目标1:确定CNVs是否导致非典型发声
新生儿期的结构,以及是否与2个月大时的ASD样行为相关;目标2:
确定非典型新生儿发声对产妇护理的影响;目的3:测量改变的
母亲护理对ASD样行为的严重程度以及CNV基因表达和表观遗传修饰的影响。
该项目的结果将揭示遗传因素和新生儿社会
与母亲的沟通导致ASD样行为的最终严重性,通过表观遗传
机制等该项目具有很高的转化价值,因为它可以提供一个新的机制基础,
了解ASD背后的基因-环境相互作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Noboru Hiroi其他文献
Noboru Hiroi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('Noboru Hiroi', 18)}}的其他基金
Predicting the developmental trajectories of cognitive and motor dimensions from preterm neonatal vocalizations
从早产儿发声预测认知和运动维度的发育轨迹
- 批准号:
10315460 - 财政年份:2021
- 资助金额:
$ 34.01万 - 项目类别:
Predicting the developmental trajectories of cognitive and motor dimensions from preterm neonatal vocalizations
从早产儿发声预测认知和运动维度的发育轨迹
- 批准号:
10463851 - 财政年份:2021
- 资助金额:
$ 34.01万 - 项目类别:
Structure and Function of Neonatal Social Communication in Genetic Mouse Models of Autism
自闭症遗传小鼠模型中新生儿社交沟通的结构和功能
- 批准号:
10220931 - 财政年份:2017
- 资助金额:
$ 34.01万 - 项目类别:
Postnatal mechanisms of cognitive development in mice
小鼠认知发展的产后机制
- 批准号:
10539977 - 财政年份:2013
- 资助金额:
$ 34.01万 - 项目类别:
Postnatal mechanisms of cognitive development in mice
小鼠认知发展的产后机制
- 批准号:
10657796 - 财政年份:2013
- 资助金额:
$ 34.01万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 34.01万 - 项目类别:
Research Grant