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

• 批准号: 10686974
• 负责人: Yohaan M Fernandes
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686974
• 关键词: Adult; Amino Acids; Arginine; Attenuated; Behavior; Behavior Disorders; Behavioral; Brain; Brain Diseases; Cell Death; Central Nervous System; 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; Fishes; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Hour; Human; Impairment; Individual; Insulin; Insulin Receptor; Leucine; Link; Mediating; Mental disorders; Mutation; Neurotransmitters; Pathway interactions; Patients; Physical environment; Pigments; Proteins; Publishing; Resources; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Social Behavior; Social Interaction; Specific qualifier value; Symptoms; System; TSC1 gene; Teratogenic effects; Testing; Tissues; Tuberous Sclerosis; United States; Work; Zebrafish; alcohol effect; alcohol exposure; alcohol sensitivity; attenuation; detection of nutrient; disabling symptom; dopaminergic neuron; dosage; embryonic alcohol exposure; environmental enrichment for laboratory animals; gene conservation; gene environment interaction; gene function; insight; mTOR Signaling Pathway; mutant; neural circuit; social; social deficits; stem; transcriptomics

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.

项目总结/摘要 精神疾病源于基因和环境之间复杂的相互作用。产前酒精暴露 是导致大脑和行为紊乱的最常见的环境输入。胎儿酒精谱系 疾病（FASD）统称为产前酒精暴露引起的所有缺陷。在美国 据估计，每100名儿童中就有1名患有FASD。社会行为受损是一种常见的和衰弱的症状 的FASD。FASD的风险是由个人的遗传基因改变的，一些缺陷与损伤有关 神经递质系统如多巴胺。然而，FASD社会赤字的确切机制是 未知 我的宿主实验室已经证明，提高mTORC 1信号可以挽救乙醇诱导的斑马鱼面部缺陷。 使用斑马鱼，我已经表明，两个小时的发育暴露于1%的乙醇（导致组织水平 约27 mM乙醇），这与已建立的啮齿动物FASD暴露相当，导致永久性 社交障碍和多巴胺功能紊乱因此，我加入了我的宿主实验室， 易患酒精诱发的社会行为缺陷。我将检验乙醇减弱 雷帕霉素靶点（mTOR）通路信号传导的总体水平，该通路调节了 多巴胺能系统和随后的社会行为。 总的来说，我的研究结果将为人类最具破坏性的疾病之一提供机械的见解， 对大脑和行为有着终生的影响