Project 2: Prenatal Alcohol Exposure (PAE) and Fetal Alcohol Spectrum Disorder (FASD)
项目2:产前酒精暴露(PAE)和胎儿酒精谱系障碍(FASD)
基本信息
- 批准号:10540966
- 负责人:
- 金额:$ 18.65万
- 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:2022-09-20 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylcysteineAddressAgonistAlcoholsAnimal ModelApplications GrantsAttenuatedBehavioralBehavioral ModelBiologicalBiological MarkersBiological ModelsCandidate Disease GeneCell LineCell modelCellsChemicalsChickCiliaClustered Regularly Interspaced Short Palindromic RepeatsCognitive deficitsCongenital AbnormalityCraniofacial AbnormalitiesDataDefectDevelopmentDigit structureDisease modelDrug ScreeningEmbryoEmbryonic DevelopmentEthanolFacultyFetal Alcohol ExposureFetal Alcohol Spectrum DisorderFetal DevelopmentFetal alcohol effectsFishesFosteringFoundationsFutureGenesGeneticGenetically Engineered MouseGoalsGrowthHeterozygoteHumanIn VitroIncidenceInterventionKnock-outKnockout MiceLibrariesLimb BudLimb DevelopmentLimb structureLiteratureMentorshipMissionModelingMolecularMolecular TargetMorphologyMusNational Institute on Alcohol Abuse and AlcoholismPathway interactionsPectoralPharmacologyPublic HealthResearchResearch PersonnelResearch Project GrantsResearch ProposalsResistanceRoleSHH geneScientistSeriesSeveritiesSignal PathwaySignal TransductionSmall Interfering RNASonic Hedgehog PathwayStainsTechnologyTeratogenic effectsTeratogensTestingTissuesTransgenic OrganismsTretinoinUnderrepresented MinorityUnderrepresented PopulationsUnited States National Institutes of HealthVisualZebrafishalcohol effectalcohol exposurealcohol researchalcohol sensitivitybasebeta Actinbrain abnormalitiesclinical practicedifferential expressionestablished cell lineexperimental studygene environment interactionhigh throughput screeningin vitro Modelin vivoin vivo Modelinnovationinsightmouse geneticsmouse modelnovelpostnatalscreeningskeletalsmall hairpin RNAsmall moleculesmall molecule librariessmoothened signaling pathwayteratogenesistranscriptome sequencing
项目摘要
Project Summary
The objective of the proposed research is to target molecular pathways involved in alcohol-induced limb/fin
defects to identify novel mechanisms with a role in FASD with the long-term goals of informing clinical practice,
and ultimately reducing the incidence and severity of Fetal Alcohol Spectrum Disorders (FASD). This objective
will be met by applying two innovative and complementary approaches that use cell, zebrafish and mouse
models to (i) genetically knockout and identify genes that rescue or exacerbate the effects of ethanol exposure,
and (ii) high throughput screening of focused chemical libraries to identify compounds that modulate the effects
of ethanol exposure. Our approach utilizes genetically modified zebrafish and mice, and the developing fin and
limb respectively, as readily examined target tissues whose molecular signaling pathways and vulnerability to
ethanol teratogenesis are well documented. This research proposal is founded on 1) strong evidence that
craniofacial abnormalities and limb defects have been observed in those identified with FASD, 2) recognition
that disruption of sonic hedgehog (Shh) signaling, a major morphogenic pathway regulating embryonic
development as a significant consequence of prenatal ethanol exposure (PAE), 3) that genetically reduced
Shh signaling results in increased vulnerability to ethanol-induced birth defects, and 4) the availability of
differentially expressed gene sets from our previous study on the effects of PAE on mouse limb development.
The hypothesis to be tested is that the identification of novel genes and compounds that can rescue
morphological and behavioral deficits elicited by PAE will reveal fundamental and novel insights into the
mechanism of ethanol-induced birth defects. This hypothesis will be tested with experiments that employ well-
established cell line, zebrafish, and mouse FASD models and will address the following Specific Aims: Aim 1
will use these in vivo and in vitro models to assess gene-environment interactions, particularly the candidate
genes whose expression was shown to be altered in ethanol-exposed mouse limb buds by our previous
ethanol RNA Seq study. Aim 2 is to utilize high-throughput screening technologies in vitro and in vivo to identify
small molecule modulators that rescue or exacerbate the effects of PAE. Small molecule compounds that
rescue or exacerbate ethanol-induced fin defects in zebrafish embryos and limbs defects in mice will be
identified. The proposed studies will be conducted by NCCU faculty and trainees under the mentorship of
UNC’s Bowles Center for Alcohol Studies researchers. In addition to expanding our understanding of ethanol’s
teratogenic mechanism of action as well as providing clues regarding genetic sensitivities and interventions for
FASD and potentially novel pathways with a role in FASD, this research project will foster state of the art
research by budding scientists from underrepresented minorities and will provide the foundation for important
FASD studies to be addressed in future grant applications/research.
项目总结
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)
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Kevin Peter Williams其他文献
Kevin Peter Williams的其他文献
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{{ truncateString('Kevin Peter Williams', 18)}}的其他基金
Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder
产前酒精暴露和胎儿酒精谱系障碍
- 批准号:
10541715 - 财政年份:2022
- 资助金额:
$ 18.65万 - 项目类别:
Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder
产前酒精暴露和胎儿酒精谱系障碍
- 批准号:
10705759 - 财政年份:2022
- 资助金额:
$ 18.65万 - 项目类别:
Project 2: Prenatal Alcohol Exposure (PAE) and Fetal Alcohol Spectrum Disorder (FASD)
项目2:产前酒精暴露(PAE)和胎儿酒精谱系障碍(FASD)
- 批准号:
10705860 - 财政年份:2022
- 资助金额:
$ 18.65万 - 项目类别:
Immune Microenvironments and Hepatocyte Growth Factor Signaling Interactions in Breast Cancer Disparities
乳腺癌差异中的免疫微环境和肝细胞生长因子信号传导相互作用
- 批准号:
10708080 - 财政年份:2017
- 资助金额:
$ 18.65万 - 项目类别:
Immune Microenvironments and Hepatocyte Growth Factor Signaling Interactions in Breast Cancer Disparities
乳腺癌差异中的免疫微环境和肝细胞生长因子信号传导相互作用
- 批准号:
10556581 - 财政年份:2017
- 资助金额:
$ 18.65万 - 项目类别:
Identification of potent and selective GLI1 inhibitors
有效且选择性 GLI1 抑制剂的鉴定
- 批准号:
8523361 - 财政年份:2013
- 资助金额:
$ 18.65万 - 项目类别:
Identification of Specific Antagonists that Bind Hedgehog and Block its Activity
鉴定结合 Hedgehog 并阻断其活性的特定拮抗剂
- 批准号:
8100944 - 财政年份:2011
- 资助金额:
$ 18.65万 - 项目类别:
The Hedgehog Pathway and Inflammatory Breast Cancer
刺猬通路和炎症性乳腺癌
- 批准号:
7666030 - 财政年份:2008
- 资助金额:
$ 18.65万 - 项目类别:
The Hedgehog Pathway and Inflammatory Breast Cancer
刺猬通路和炎症性乳腺癌
- 批准号:
7427272 - 财政年份:2008
- 资助金额:
$ 18.65万 - 项目类别:
The Hedgehog Pathway and Inflammatory Breast Cancer
刺猬通路和炎症性乳腺癌
- 批准号:
7922003 - 财政年份:2008
- 资助金额:
$ 18.65万 - 项目类别:
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