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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：
Kevin Peter Williams
金额：
$ 18.65万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
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：
https://reporter.nih.gov/project-details/10540966
关键词：
Acetylcysteine Address Agonist Alcohols Animal Model Applications Grants Attenuated Behavioral Behavioral Model Biological Biological Markers Biological Models Candidate Disease Gene Cell Line Cell model Cells Chemicals Chick Cilia Clustered Regularly Interspaced Short Palindromic Repeats Cognitive deficits Congenital Abnormality Craniofacial Abnormalities Data Defect Development Digit structure Disease model Drug Screening Embryo Embryonic Development Ethanol Faculty Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Development Fetal alcohol effects Fishes Fostering Foundations Future Genes Genetic Genetically Engineered Mouse Goals Growth Heterozygote Human In Vitro Incidence Intervention Knock-out Knockout Mice Libraries Limb Bud Limb Development Limb structure Literature Mentorship Mission Modeling Molecular Molecular Target Morphology Mus National Institute on Alcohol Abuse and Alcoholism Pathway interactions Pectoral Pharmacology Public Health Research Research Personnel Research Project Grants Research Proposals Resistance Role SHH gene Scientist Series Severities Signal Pathway Signal Transduction Small Interfering RNA Sonic Hedgehog Pathway Stains Technology Teratogenic effects Teratogens Testing Tissues Transgenic Organisms Tretinoin Underrepresented Minority Underrepresented Populations United States National Institutes of Health Visual Zebrafish alcohol effect alcohol exposure alcohol research alcohol sensitivity base beta Actin brain abnormalities clinical practice differential expression established cell line experimental study gene environment interaction high throughput screening in vitro Model in vivo in vivo Model innovation insight mouse genetics mouse model novel postnatal screening skeletal small hairpin RNA small molecule small molecule libraries smoothened signaling pathway teratogenesis transcriptome 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