Influence of early developmental ethanol exposure on genes, the mTOR signaling pathway and behavior

早期发育乙醇暴露对基因、mTOR 信号通路和行为的影响

基本信息

批准号：
9892708
负责人：
Yohaan M Fernandes
金额：
$ 11.21万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892708
关键词：
Adult Alcohols Amino Acids Arginine Attenuated Behavior Behavior Disorders Behavioral Brain Diseases Cell Death Child Complex Congenital Abnormality Data Defect Development Diagnosis Disease Dopamine Dopamine Receptor Dose Embryo Environment Ethanol Etiology Exposure to FRAP1 gene Face Fertilization Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Diseases Fishes Functional disorder Genes Genetic Genetic Predisposition to Disease Genotype Hour Human Impairment Individual Insulin Insulin Receptor Leucine Life Link Mediating Mental disorders Mutation Neuraxis Neurotransmitters Pathway interactions Patients Physical environment Pigments Play Proteins Publishing Raptors Resources Risk Rodent Role Signal Pathway Signal Transduction Social Behavior Social Interaction Symptoms System TSC1 gene Teratogenic effects Testing Tissues Transgenic Organisms Tuberous sclerosis protein complex United States Work Zebrafish alcohol effect alcohol exposure alcohol sensitivity attenuation brain behavior cohesion detection of nutrient disabling symptom dopaminergic neuron dosage environmental enrichment for laboratory animals gene conservation gene environment interaction gene function insight mutant receptor function social social deficits stem transcriptomics

项目摘要

Project Summary / Abstract Mental illness stems from intricate interactions between genes and the environment. Prenatal alcohol exposure is most common environmental input that leads to disorders of the brain and behavior. Fetal Alcohol Spectrum Disorder (FASD) collectively describes all the defects caused by prenatal alcohol exposure. In the United States it is estimated that 1 in 100 children have FASD. Impaired social behavior is a frequent and debilitating symptom of FASD. The risk of FASD is modified by an individual's genetics, with some deficits being linked to impairments of neurotransmitter systems such as dopamine. However, the exact mechanisms for FASD social deficits are unknown. My host lab has shown that elevating mTORC1 signaling rescues ethanol-induced facial defects in zebrafish. Using zebrafish, I have shown that a two-hour developmental exposure to 1% ethanol (resulting in tissue levels of approximately 27 mM ethanol), which is comparable to established rodent FASD exposure leads to permanent social deficits and disrupted dopamine functioning. Thus, I joined my host lab to characterize the genetic predisposition to ethanol-induced social behavior deficits. I will test the hypothesis that ethanol attenuates the overall level of mechanistic target-of-rapamycin (mTOR) pathway signaling which regulates development of the dopaminergic system and, subsequently social behavior. Collectively my results will provide mechanistic insight into one of the most devastating human disorders which, has a life-long impact on the brain and behavior.

项目摘要 /摘要精神疾病源于基因与环境之间的复杂相互作用。产前酒精暴露是最常见的环境输入，导致大脑和行为障碍。胎儿酒精谱疾病（FASD）统称是由产前酒精暴露引起的所有缺陷。在美国据估计，有100名儿童中有1个患有FASD。社会行为受损是一种频繁而令人衰弱的症状 Fasd。 FASD的风险通过个人的遗传学修改，有些缺陷与损害有关神经递质系统（例如多巴胺）但是，FASD社会缺陷的确切机制是未知。我的主机实验室表明，提升MTORC1信号传导挽救了斑马鱼中乙醇引起的面部缺陷。使用斑马鱼，我已经证明了两个小时的发育暴露于1％乙醇（导致组织水平大约27毫米乙醇），与已建立的啮齿动物FASD暴露相当，导致永久性社会缺陷和多巴胺功能中断。因此，我加入了主机实验室以表征遗传乙醇引起的社会行为缺陷的倾向。我将检验以下假设，即乙醇会减弱机械靶标性靶标（MTOR）途径的总体水平，该途径调节了调节的发展多巴胺能系统，随后是社会行为。总的来说，我的结果将为最毁灭性的人类疾病之一提供机械洞察力的见解。对大脑和行为有终身影响。