RAX, PKR and ethanol neurotoxicity

RAX、PKR 和乙醇神经毒性

• 批准号: 8670678
• 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
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670678
• 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; 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

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) 是由母亲在怀孕期间饮酒引起的一系列永久性出生缺陷。最近估计，美国学童中 FASD 的患病率高达 2-5%，比唐氏综合症和自闭症更常见。每年与 FASD 相关的费用超过 60 亿美元。 NIAAA 2009-2014年战略计划中的重要目标是确定大脑中乙醇毒性的机制并确定有效的治疗靶点。 中枢神经系统（CNS）损伤是 FASD 患者的一个主要特征。小脑是中枢神经系统中对乙醇毒性最敏感的区域之一。神经元损失是乙醇最有害的影响之一，也是导致 FASD 中观察到的许多行为缺陷的原因。在动物模型中，婴儿啮齿动物在大脑生长突增期（出生后）的一部分期间接触乙醇 第 4 至 9 天 (PD)，相当于人类妊娠晚期 - 导致小脑浦肯野神经元和颗粒神经元显着损失。然而，乙醇引起发育中小脑神经元损失的潜在机制仍不清楚。本研究的目的是确定乙醇神经毒性的机制以及预防和治疗 FASD 的新靶点。 双链RNA（dsRNA）激活蛋白激酶（PKR）通过调节多种下游靶蛋白和信号通路来组织细胞自卫系统，以应对不同的理化应激或病毒感染。在理化应激条件下，PKR 的胞内激活剂 RAX 激活会导致蛋白质合成抑制和细胞凋亡，并与许多神经退行性疾病的发病机制有关。 该研究的中心假设是 RAX 介导的 PKR 激活调节发育中小脑中乙醇诱导的神经元损失。 具体目标 1：研究通过 RAX/PKR 相互作用激活 PKR 是否可以调节小鼠发育中小脑中乙醇诱导的神经元凋亡。 具体目标 2：确定通过靶向 RAX 或 PKR 表达或通过 PKR 抑制剂抑制 PKR 是否可以减轻小鼠发育中小脑中乙醇诱导的神经元损失。 具体目标 3：确定 RAX+/- 小鼠、N-PKR-/- 小鼠或注射 PKR 抑制剂的小鼠是否对乙醇诱导的小脑行为功能障碍具有更强的抵抗力。