Role of Siah1 in ethanol-induced apoptosis and teratogenesis
Siah1 在乙醇诱导的细胞凋亡和致畸中的作用
基本信息
- 批准号:9108234
- 负责人:
- 金额:$ 34.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-05 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAddressAlcohol consumptionAlcoholsAntioxidantsApoptosisApoptoticBrainBrain regionCell Cycle ArrestCell DeathCell LineCell physiologyCellsCessation of lifeCongenital AbnormalityDataDevelopmentDisease modelEP300 geneEmbryoEthanolFamilyFetal Alcohol ExposureFetal Alcohol Spectrum DisorderGoalsHumanIntakeKnockout MiceKnowledgeLaboratoriesLifeMAPK8 geneMediatingMental RetardationMissionMolecularMolecular TargetMusNeural Crest CellNeuronsNuclear TranslocationOralPathogenesisPathway interactionsPhosphorylationPopulationPreventionPrevention strategyPreventive InterventionProteinsPublic HealthResearchRoleSignal PathwaySignal TransductionSiteSmall Interfering RNAStagingTP53 geneTertiary Protein StructureTestingTherapeuticTherapeutic InterventionThird Pregnancy TrimesterWorkalcohol effectalcohol exposurebaseeffective interventionembryo culturefetalin vivoinnovationinsightknock-downmRNA Expressionmalformationmembernon-geneticnovel strategiesnovel therapeuticsp53 Signaling Pathwaypreventprotein expression
项目摘要
DESCRIPTION (provided by applicant): Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However, there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. Continued existence of this gap represents an important problem because, until it is filled, understanding of ethanol- induced apoptosis that leads to teratogenesis will remain largely incomprehensible. Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific proteins involved in apoptosis. The overall objective of this particular proposal is to establish Siah1, a member of the seven in absentia homology family, as a feasible target for the prevention of ethanol-induced apoptosis and teratogenesis. The central hypothesis to be tested is that Siah1 mediates ethanol-induced apoptosis in neural crest cells (NCCs) by activating the p53 pathway and that the inhibition of Siah1-mediated apoptosis can prevent ethanol-induced teratogenesis. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis, the following specific aims will be addressed: Aim1: To characterize the role of Siah1 in ethanol-induced apoptosis in NCCs. We will determine the effects of ethanol on Siah1 mRNA and protein expression, and investigate the potential of ethanol to promote Siah1 nuclear translocation and induce apoptosis. Aim2: To test the hypothesis that Siah1 mediates ethanol-induced apoptosis in NCCs by activating the p53 pathway. This will be accomplished by determining the role of Siah1 in ethanol-induced activation of p53 signaling pathway and in the induction of p53 downstream proapoptotic proteins and apoptosis. Aim3: To define the role of the inhibition of Siah1 function in conferring protection against ethanol-induced teratogenesis. This will be accomplished by using whole embryo culture, Siah1 knockout mice and an oral intake FASD model. We will determine whether knocking down Siah1 diminishes ethanol-induced malformations in cultured mouse embryos and whether Siah1 deficiency in Siah1-/- mouse embryos can confer in vivo protection against ethanol-induced teratogenesis. The proposed work is innovative, because it focuses on a novel approach, targeting specific proteins directly involved in the apoptotic pathway, to preventing ethanol-induced apoptosis and teratogenesis. The theoretical concept described in the application is also highly innovative because this is the first study attempting to prevent ethanol-induced apoptosis and teratogenesis specifically through the newly recognized actions of Siah1 in apoptosis. The results from this study will be significant, because the insights gained by the accomplishment of these aims will help in elucidating the role of Siah1 in mediating ethanol- induced teratogenesis. They are also expected to yield strategies for the prevention of ethanol's teratogenesis and to fundamentally advance the field of FASD research.
描述(由申请人提供):产前乙醇暴露是已知的导致智力迟钝的主要原因。越来越多的证据表明,过度的细胞死亡是乙醇诱导的出生缺陷发病机制的主要组成部分。然而,在理解乙醇如何导致胚胎细胞凋亡方面存在根本性的差距。这一空白的持续存在代表了一个重要的问题,因为直到它被填补,对乙醇诱导的细胞凋亡导致致畸的理解将在很大程度上仍然是不可理解的。我们的长期目标是针对乙醇致畸的有效策略的发展;通过靶向参与细胞凋亡的特定蛋白来预防乙醇诱导的细胞凋亡的策略。本特别提案的总体目标是建立Siah1作为7缺失同源家族的成员,作为预防乙醇诱导的细胞凋亡和致畸的可行靶点。待验证的中心假设是Siah1通过激活p53通路介导乙醇诱导的神经嵴细胞(NCCs)凋亡,抑制Siah1介导的凋亡可以预防乙醇诱导的畸胎化。我们的假设是在我们实验室产生的强有力的初步数据的基础上制定的。为了验证我们的假设,以下具体目标将被解决:目的1:表征Siah1在乙醇诱导的NCCs细胞凋亡中的作用。我们将确定乙醇对Siah1 mRNA和蛋白表达的影响,并研究乙醇促进Siah1核易位和诱导细胞凋亡的可能性。目的2:验证Siah1通过激活p53通路介导乙醇诱导的NCCs细胞凋亡的假说。这将通过确定Siah1在乙醇诱导的p53信号通路激活和p53下游促凋亡蛋白诱导和凋亡中的作用来实现。目的3:明确抑制Siah1功能在保护胎儿免受乙醇诱导的畸胎症中的作用。这将通过全胚胎培养、Siah1敲除小鼠和口服摄取FASD模型来完成。我们将确定敲除Siah1是否会减少培养小鼠胚胎中乙醇诱导的畸形,以及Siah1-/-小鼠胚胎中Siah1缺失是否能在体内保护小鼠免受乙醇诱导的畸形。这项工作是创新的,因为它侧重于一种新的方法,针对直接参与凋亡途径的特定蛋白质,来防止乙醇诱导的细胞凋亡和致畸。该申请中描述的理论概念也具有高度创新性,因为这是第一个试图通过新认识的Siah1在细胞凋亡中的作用来特异性地预防乙醇诱导的细胞凋亡和致畸的研究。这项研究的结果将是重要的,因为完成这些目标所获得的见解将有助于阐明Siah1在介导乙醇诱导的致畸中的作用。他们还有望产生预防乙醇致畸的策略,并从根本上推进FASD研究领域。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
In vivo epidermal migration requires focal adhesion targeting of ACF7.
- DOI:10.1038/ncomms11692
- 发表时间:2016-05-24
- 期刊:
- 影响因子:16.6
- 作者:Yue J;Zhang Y;Liang WG;Gou X;Lee P;Liu H;Lyu W;Tang WJ;Chen SY;Yang F;Liang H;Wu X
- 通讯作者:Wu X
{{
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 }}
Shao-yu Chen其他文献
Shao-yu Chen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('Shao-yu Chen', 18)}}的其他基金
Role of exosomes in the coordinated migration of neural crest cells and placodes and ethanol-induced teratogenesis
外泌体在神经嵴细胞和基板协调迁移以及乙醇诱导的致畸中的作用
- 批准号:
10677038 - 财政年份:2020
- 资助金额:
$ 34.07万 - 项目类别:
Role of exosomes in the coordinated migration of neural crest cells and placodes and ethanol-induced teratogenesis
外泌体在神经嵴细胞和基板协调迁移以及乙醇诱导的致畸中的作用
- 批准号:
10463617 - 财政年份:2020
- 资助金额:
$ 34.07万 - 项目类别:
Role of exosomes in the coordinated migration of neural crest cells and placodes and ethanol-induced teratogenesis
外泌体在神经嵴细胞和基板协调迁移以及乙醇诱导的致畸中的作用
- 批准号:
10221505 - 财政年份:2020
- 资助金额:
$ 34.07万 - 项目类别:
Sulforaphane-mediated epigenetic modulation of ethanol-induced apoptosis and teratogenesis
萝卜硫素介导的乙醇诱导的细胞凋亡和致畸的表观遗传调节
- 批准号:
8978014 - 财政年份:2016
- 资助金额:
$ 34.07万 - 项目类别:
Enhancer-mediated transcriptional dysregulation in neural crest cells and ethanol-induced teratogenesis
神经嵴细胞增强子介导的转录失调和乙醇诱导的致畸
- 批准号:
10625855 - 财政年份:2016
- 资助金额:
$ 34.07万 - 项目类别:
Enhancer-mediated transcriptional dysregulation in neural crest cells and ethanol-induced teratogenesis
神经嵴细胞增强子介导的转录失调和乙醇诱导的致畸
- 批准号:
10056415 - 财政年份:2016
- 资助金额:
$ 34.07万 - 项目类别:
Role of microRNAs in Ethanol-induced Apoptosis and Teratogenesis
microRNA 在乙醇诱导的细胞凋亡和致畸中的作用
- 批准号:
8703582 - 财政年份:2013
- 资助金额:
$ 34.07万 - 项目类别:
Role of microRNAs in Ethanol-induced Apoptosis and Teratogenesis
microRNA 在乙醇诱导的细胞凋亡和致畸中的作用
- 批准号:
8882187 - 财政年份:2013
- 资助金额:
$ 34.07万 - 项目类别:
Role of microRNAs in Ethanol-induced Apoptosis and Teratogenesis
microRNA 在乙醇诱导的细胞凋亡和致畸中的作用
- 批准号:
8436097 - 财政年份:2013
- 资助金额:
$ 34.07万 - 项目类别:
Role of Siah1 in ethanol-induced apoptosis and teratogenesis
Siah1 在乙醇诱导的细胞凋亡和致畸中的作用
- 批准号:
8232664 - 财政年份:2012
- 资助金额:
$ 34.07万 - 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:
$ 34.07万 - 项目类别:
Fellowship
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:
$ 34.07万 - 项目类别:
Research Grant
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:
$ 34.07万 - 项目类别:
Continuing 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:
$ 34.07万 - 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:
$ 34.07万 - 项目类别:
Standard Grant
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:
$ 34.07万 - 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:
$ 34.07万 - 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:
$ 34.07万 - 项目类别:
EU-Funded
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:
$ 34.07万 - 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:
$ 34.07万 - 项目类别:
Research Grant