RAX, PKR and ethanol neurotoxicity

RAX、PKR 和乙醇神经毒性

基本信息

批准号：
8851454
负责人：
Gang Chen
金额：
$ 25.21万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2012-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851454
关键词：
Affect Animal Behavior Animal Model Animals Apoptosis Apoptotic Area Autistic Disorder Behavioral Binding Brain Cells Cerebellum Child Congenital Abnormality Cytoplasmic Granules Development Disease Dominant-Negative Mutation Double-Stranded RNA Down Syndrome Ethanol Ethanol toxicity Exposure to Fetal Alcohol Spectrum Disorder Functional disorder Goals Growth Health Human In Vitro Infant Inhibition of Apoptosis Investigation Learning Disabilities Mediating Mental Retardation Molecular Mus National Institute on Alcohol Abuse and Alcoholism Nerve Degeneration Nervous System Trauma Neuraxis Neurodegenerative Disorders Neurons Outcome Oxidative Stress Pathogenesis Patients Play Population Prevalence Prevention Protein Synthesis Inhibition Proteins Psyche structure Public Health Reporting Resistance Rodent Role Schools Series Severities Signal Pathway Social Problems Strategic Planning Stress System Testing Third Pregnancy Trimester Transgenic Mice United States Virus Diseases Weight alcohol consumption during pregnancy alcohol effect alcohol exposure alcohol sensitivity behavior test behavioral impairment behavioral study cell type cost disability eIF-2 Kinase effective therapy inhibitor/antagonist innovation mouse model neuron apoptosis neuron loss neurotoxicity novel novel strategies postnatal response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorders (FASD) are a range of permanent birth defects caused by maternal alcohol consumption during pregnancy. The prevalence of FASD in populations of younger school children is recently estimated as high as 2-5% in the United State and is more common than Down syndrome and autism. FASD-related costs are more than $6 billion annually. Identification of the mechanism of ethanol toxicity in the brain and determination of the effective therapeutic target(s) are cited as importat goals in the NIAAA Strategic Plan for 2009-2014. Central nervous system (CNS) damage is a major feature observed in FASD patients. The cerebellum is one of the most sensitive areas in the CNS to ethanol toxicity. Neuronal loss is one of the most deleterious effects of ethanol and is responsible for many of the behavioral deficits observed in FASD. In the animal model, exposure of infant rodents to ethanol during a portion of the brain growth spurt period - postnatal day (PD) 4 to 9, equivalent to the human third trimester - causes a significant loss of cerebellum Purkinje and granule neurons. However, the underlying mechanism for ethanol-induced neuronal loss in the developing cerebellum is still largely unclear. The goal of this proposed study is to identify the mechanism underlying ethanol neurotoxicity and the novel target(s) for the prevention and treatment of FASD. The double-stranded RNA (dsRNA)-activated protein kinase (PKR) organizes the cellular self-defense system in response to diverse physiochemical stresses or viral infection by regulating a variety of downstream target proteins and signal pathways. Activation of PKR by its intracellular activator RAX under physiochemical stress conditions leads to protein synthesis inhibition as well as apoptosis and has been implicated in the pathogenesis of a number of neurodegenerative diseases. The central hypothesis of the proposed study is that RAX-mediated PKR activation regulates ethanol- induced neuronal loss in the developing cerebellum. Specific Aim 1: To investigate whether PKR activation through RAX/PKR interaction regulates ethanol- induced neuronal apoptosis in the developing cerebellum of the mouse. Specific Aim 2: To determine whether inhibition of PKR by targeting RAX or PKR expression or by PKR inhibitors alleviates ethanol-induced neuronal loss in the developing cerebellum of the mouse. Specific Aim 3: To determine whether RAX+/- mice, N-PKR-/- mice or PKR-inhibitor-injected mice are more resistant to ethanol-induced cerebellar behavioral dysfunction.

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是由孕妇在怀孕期间孕妇饮酒引起的一系列永久性出生缺陷。最近，在美国，年轻小学生人群中FASD的患病率高达2-5％，比唐氏综合症和自闭症更为普遍。与FASD相关的成本每年超过60亿美元。在2009 - 2014年的NIAAA战略计划中，将乙醇毒性机理的鉴定和有效治疗靶标的确定被认为是进口目标。中枢神经系统（CNS）损伤是FASD患者观察到的主要特征。小脑是中枢神经系统对乙醇毒性最敏感的区域之一。神经元丧失是乙醇最有害的作用之一，并且负责FASD中观察到的许多行为缺陷。在动物模型中，婴儿啮齿动物在大脑生长时期的一部分中暴露于乙醇 - 产后天（PD）4至9，相当于人类三个月 - 造成小脑Purkinje和颗粒神经元的显着丧失。然而，在发育中的小脑中，乙醇诱导的神经元丧失的基本机制仍然在很大程度上尚不清楚。这项拟议的研究的目的是确定乙醇神经毒性的基础机制和预防和治疗FASD的新目标。双链RNA（DSRNA）激活的蛋白激酶（PKR）通过调节多种下游靶蛋白和信号途径来响应各种生理化学应力或病毒感染，以响应各种生理化学应力或病毒感染。 PKR通过其细胞内活化剂RAX在生理应力条件下的激活导致蛋白质合成抑制和凋亡，并且与许多神经退行性疾病的发病机理有关。拟议的研究的中心假设是RAX介导的PKR激活调节发育中的小脑中乙醇诱导的神经元丧失。具体目的1：研究通过RAX/PKR相互作用通过RAX/PKR相互作用激活是否会调节乙醇诱导的小鼠发育中的神经元凋亡。具体目标2：确定通过靶向RAX或PKR表达或PKR抑制剂来抑制PKR是否减轻了乙醇诱导的小鼠的神经元损失。特定目标3：确定RAX +/-小鼠，N-PKR - / - 小鼠或PKR抑制剂注射的小鼠是否对乙醇诱导的小脑行为功能障碍更具耐药性。