The Neuroprotective Effects of Sulforaphane in VPA-Induced Models of Autism
萝卜硫素对 VPA 诱导的自闭症模型的神经保护作用
基本信息
- 批准号:10373324
- 负责人:
- 金额:$ 23.98万
- 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:2022-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdolescentAnimalsAntioxidantsBehaviorBehavioralBehavioral ModelBiological AssayBrainBroccoli - dietaryChemical ModelsChemicalsClinical TrialsCongenital AbnormalityDefense MechanismsDevelopmentDevelopmental DisabilitiesDrug Metabolic DetoxicationEmbryoEnvironmentEnvironmental PollutantsEnvironmental PollutionEnvironmental Risk FactorExposure toFetal DevelopmentFetusGenesGeneticHomeostasisHumanImpairmentIncidenceKnockout MiceLinkMammalsMediatingMicroelectrodesModelingMonitorMusNF-E2-related factor 2Neurodevelopmental DisorderNitrogenOrganoidsOutcomeOxidative StressOxygenPathway interactionsPharmacologic SubstancePhenotypePhytochemicalPregnant WomenPrevalencePreventive measureProductionResearchRiskRunningSocial InteractionStandardizationStudy modelsSulforaphaneSupplementationTestingToxinTranscriptional RegulationUnited StatesUp-RegulationValproic AcidWorkautism spectrum disorderbehavioral outcomecombatconfocal imagingcruciferous vegetabledevelopmental diseasediagnostic criteriadisabilitymicrophysiology systemmouse modelneural circuitneural networkneurodevelopmentoxidative damagepollutantprenatalprenatal exposurepreventrepetitive behaviorresiliencesocial communicationsynaptogenesistoxicanttranscription factor
项目摘要
Many environmental pollutants alter physiological homeostasis, and this dysregulation is especially harmful
when it occurs embryonically. Unfortunately, pregnant women are commonly exposed to multiple environmental
contaminants, which increase the risk of a variety of developmental disorders. For example, several pollutants
are known to disrupt neural development. In fact, animal studies show causal links between some pollutants and
development of behavior that is typical of autism spectrum disorders (ASD), a group of devastating
neurodevelopmental disorders that have become all too common in humans. In fact, neurodevelopmental
disorders, such as autism spectrum disorders (ASD), are the fastest growing developmental disabilities in the
United States. In 2016 the prevalence of ASD was nearly 2% and its incidence has doubled in the last 20 years.
Indeed, it is widely recognized that genetic and environmental factors, such as exposure to pollutants, interact
to increase the risk of developing an ASD. While we have evolved defense mechanisms to mitigate the effects
of natural toxins, they are insufficient to combat today’s ever-increasing environmental contamination. However,
if we can augment our endogenous preventative mechanisms, we can prevent pollutant-induced disabilities. We
recently determined in the mouse model that pollutant-exposed fetuses supplemented with sulforaphane, a
derivative of broccoli, have less frequent and less severe birth defects relative to embryos exposed to only
pollutants. This project will test the generality of that rescue effect by determining the mechanisms through which
we can prevent chemical-induced alterations in neural circuitry and associated behaviors. Fetal exposure to
valproic acid (VPA) is known to cause ASD in humans and autism-like behavior in mice. Here we will exploit this
model to understand the mechanisms of resilience that sulforaphane upregulates to protect the fetus from
developing autism. Specifically, using human brain organoids we will establish the mechanisms by which it
reduces VPA-mediated alterations in neural circuit development. We will then assess the impact of sulforaphane
on VPA-induced behavioral outcomes in the VPA mouse model. This research benefits from the combined
strengths of a robust model of chemical-induced ASD, a human brain microphysiological system, and a mouse
behavioral model. This unprecedented approach will allow us to identify preventative measures that facilitate
normal neural circuit development in a toxic environment.
许多环境污染物改变了生理稳态,这种失调尤其有害
当它发生在胚胎时。不幸的是,孕妇通常暴露于多种环境中,
污染物,这增加了各种发育障碍的风险。例如,几种污染物
会扰乱神经发育事实上,动物研究表明,一些污染物和
自闭症谱系障碍(ASD)的典型行为发展,一组毁灭性的
神经发育障碍已经在人类中变得非常普遍。事实上,
自闭症谱系障碍(ASD)是世界上增长最快的发育障碍,
美国的2016年,ASD的患病率接近2%,其发病率在过去20年中翻了一番。
事实上,人们普遍认识到,遗传和环境因素,如接触污染物,
会增加患自闭症的风险虽然我们进化出了防御机制来减轻
尽管这些方法对天然毒素的使用量很大,但它们不足以对抗当今日益严重的环境污染。然而,在这方面,
如果我们能够加强我们的内在预防机制,我们就能够防止污染引起的残疾。我们
最近在小鼠模型中确定,暴露于污染物的胎儿补充萝卜硫素,
西兰花的衍生物,相对于只暴露于西兰花的胚胎,
污染物这个项目将通过确定通过何种机制来测试这种救援效果的普遍性,
我们可以防止化学物质引起的神经回路和相关行为的改变。胎儿暴露于
已知丙戊酸(VPA)引起人类的ASD和小鼠的自闭症样行为。在这里,我们将利用这一点
模型来了解萝卜硫素上调以保护胎儿免受
发展成自闭症具体来说,使用人脑类器官,我们将建立它的机制,
减少VPA介导的神经回路发育改变。然后我们将评估萝卜硫素的影响
VPA小鼠模型中VPA诱导的行为结果。这项研究得益于
化学诱导的ASD、人脑微生理系统和小鼠的稳健模型的优势
行为模型这种前所未有的方法将使我们能够确定预防措施,
神经回路在有毒环境中的正常发育
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 }}
Karen A Litwa其他文献
Karen A Litwa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('Karen A Litwa', 18)}}的其他基金
The Neuroprotective Effects of Sulforaphane in VPA-Induced Models of Autism
萝卜硫素对 VPA 诱导的自闭症模型的神经保护作用
- 批准号:
10559598 - 财政年份:2022
- 资助金额:
$ 23.98万 - 项目类别:
Vesicular Mechanisms for Lysosomal Delivery of Synaptic Vesicle Proteins
突触小泡蛋白溶酶体递送的囊泡机制
- 批准号:
7514422 - 财政年份:2007
- 资助金额:
$ 23.98万 - 项目类别:
Vesicular Mechanisms for Lysosomal Delivery of Synaptic Vesicle Proteins
突触小泡蛋白溶酶体递送的囊泡机制
- 批准号:
7330088 - 财政年份:2007
- 资助金额:
$ 23.98万 - 项目类别:
相似海外基金
Enhancing Structural Competency in School-Based Health Centers to Address LGBTQ+ Adolescent Health Equity
增强校本健康中心的结构能力,以解决 LGBTQ 青少年健康公平问题
- 批准号:
10608426 - 财政年份:2023
- 资助金额:
$ 23.98万 - 项目类别:
Application and feasability of a brief digital screening tool to address parental and adolescent tobacco and electronic cigarette use in pediatric medical care - a pilot study
简短的数字筛查工具的应用和可行性,以解决儿科医疗中父母和青少年烟草和电子烟的使用问题 - 一项试点研究
- 批准号:
486580 - 财政年份:2022
- 资助金额:
$ 23.98万 - 项目类别:
Studentship Programs
Co-design of an intervention to address alcohol use among adolescent boys and young men in Tanzania
共同设计一项干预措施,解决坦桑尼亚青春期男孩和年轻男性的饮酒问题
- 批准号:
MR/V032380/1 - 财政年份:2022
- 资助金额:
$ 23.98万 - 项目类别:
Research Grant
Complex intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition: A RCT in rural and urban South Africa
优化青少年孕前体重指数以解决营养不良的双重负担的复杂干预措施:南非农村和城市的随机对照试验
- 批准号:
MR/V005790/1 - 财政年份:2021
- 资助金额:
$ 23.98万 - 项目类别:
Research Grant
Application of a brief digital screening tool to address parental and adolescent tobacco and electronic cigarette use in pediatric medical care
应用简短的数字筛查工具来解决儿科医疗中父母和青少年烟草和电子烟的使用问题
- 批准号:
455984 - 财政年份:2021
- 资助金额:
$ 23.98万 - 项目类别:
Operating Grants
Complex intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition: A RCT in rural and urban South Africa
优化青少年孕前体重指数以解决营养不良的双重负担的复杂干预措施:南非农村和城市的随机对照试验
- 批准号:
MR/V005790/2 - 财政年份:2021
- 资助金额:
$ 23.98万 - 项目类别:
Research Grant
Development of the Cannabis Actions and Practices (CAP): A Parent-Focused Intervention to Address Adolescent Marijuana Use
大麻行动和实践 (CAP) 的发展:以家长为中心的干预措施,解决青少年大麻使用问题
- 批准号:
10057761 - 财政年份:2020
- 资助金额:
$ 23.98万 - 项目类别:
Development of the Cannabis Actions and Practices (CAP): A Parent-Focused Intervention to Address Adolescent Marijuana Use
大麻行动和实践 (CAP) 的发展:以家长为中心的干预措施,解决青少年大麻使用问题
- 批准号:
10213683 - 财政年份:2020
- 资助金额:
$ 23.98万 - 项目类别:
Targeted interventions to address the multi-level effects of gender-based violence on PrEP uptake and adherence among adolescent girls and young women in Kenya
有针对性的干预措施,以解决性别暴力对肯尼亚少女和年轻妇女接受和坚持 PrEP 的多层面影响
- 批准号:
9403567 - 财政年份:2017
- 资助金额:
$ 23.98万 - 项目类别:
Designing targeted interventions to address HIV vulnerabilities and improve clinical outcomes among conflict affected adolescent girls and young women under 25 in Northern Uganda
设计有针对性的干预措施,以解决乌干达北部受冲突影响的少女和 25 岁以下年轻妇女的艾滋病毒脆弱性并改善临床结果
- 批准号:
356145 - 财政年份:2016
- 资助金额:
$ 23.98万 - 项目类别:
Operating Grants