Molecular mechanism of ADNF and ADNP peptides in neuroprotection to alcohol

ADNF和ADNP肽对酒精神经保护的分子机制

• 批准号: 7194545
• 负责人: YOUSSEF SARI
• 金额: $ 17.99万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194545
• 关键词: Alcohol consumption; Alcoholic Intoxication; Alcohols; Amino Acids; Apoptosis; Apoptotic; Biological Models; Body Weight; Brain; C57BL/6 Mouse; Cell Death; Cells; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diet; Dose; Embryo; Fetal Alcohol Exposure; Fetal Alcohol Syndrome; Fetal Death; Figs - dietary; Genes; Glutathione Disulfide; Goals; Growth; Human; In Vitro; Injection of therapeutic agent; Intraperitoneal Injections; Kinetics; L Forms; Laboratories; Light; Liquid substance; Methods; Mitochondria; Modeling; Molecular; Molecular Conformation; Molecular Mechanisms of Action; Mus; NAPVSIPQ peptide; National Institute of Child Health and Human Development; Neuraxis; Neurons; Outcome; Oxidative Stress; Pathway interactions; Peptides; Pregnancy; Prevention; Process; Prosencephalon; Protein Kinase C; Protein p53; Proteins; Proteomics; Regulation; Regulatory Pathway; Research; Research Personnel; Signal Pathway; Signal Transduction; Staging; TP53 gene; Testing; Therapeutic; Time; United States National Institutes of Health; Weight; Work; alcohol abuse therapy; alcohol effect; alcohol exposure; base; caspase-3; cytochrome c; day; drinking; enantiomer; fetal; in vivo; intraperitoneal; neuroprotection; neurotrophic factor; prenatal; prevent; programs; protective effect; protein expression; research study; size

DESCRIPTION (provided by applicant): Alcohol has been known to impede the growth of the central nervous system. Previous studies have focused on the identification of antagonists for the specific actions of alcohol. In turn, these studies have investigated the possible prevention of prenatal alcohol exposure effects with peptides that were previously shown to be involved in neuroprotection in vitro and in vivo. Among these peptides, an active fragment of a nine amino acids (SALLRSIPA), SAL or ADNF-9, was the shortest sequence that mimicked the potent neuroprotective ability of activity-dependent neurotrophic factor (ADNF). Another peptide, NAP, contains eight amino acids (NAPVSIPQ) and is considered an ADNF-9-like fragment of activity-dependent neuroprotective protein (ADNP). The protective effects of NAP and SAL/ADNF-9 have been investigated particularly in vitro. The in vivo studies conducted at the NIH-NICHD using prenatal intraperitoneal injections of alcohol and peptides have demonstrated that the peptides prevented alcohol induced fetal death. In vivo studies from our laboratories that used a liquid diet paradigm as a model for moderate alcohol drinking, have demonstrated neuroprotective effects of NAP and SAL/ADNF-9 peptides by morphological analyses. The cellular mechanism of the neuroprotective effects of NAP and SAL/ADNF-9 peptides are still not fully characterized. It is unknown whether NAP and SAL/ADNF-9 act through proliferation or apoptosis in a fetal alcohol exposure model. The in vitro studies conducted in ours and others laboratories suggested that these peptides may act through the prevention of apoptosis. Based on the in vitro findings, we hypothesize that NAP and SAL/ADNF-9 peptides induce neuroprotection against the insult of prenatal alcohol exposure through apoptotic regulation. Since the molecular mechanisms of NAP and SAL/ADNF-9 against the effects of prenatal alcohol exposure are not yet elucidated, we aim in the proposed experiments to determine the precise temporal organization of the signaling outcomes and delineate pathways of neuroprotection for both NAP and SAL/ADNF-9 peptides. The data generated from the proposed experiments will provide information about NAP and SAL/ADNF-9 intracellular targets. This data will shed light on the mechanisms governing brain ontogeny and will pave the path toward potential therapeutics against developmental insults associated with prenatal alcohol exposure.

描述（由申请人提供）：已知酒精会阻碍中枢神经系统的生长。以前的研究主要集中在确定酒精的具体行动的拮抗剂。反过来，这些研究调查了可能的预防产前酒精暴露的影响与肽，以前被证明是参与在体外和体内的神经保护。在这些肽中，9个氨基酸的活性片段（SALLRSIPA），SAL或ADNF-9是模拟活性依赖性神经营养因子（ADNF）的有效神经保护能力的最短序列。另一种肽NAP含有8个氨基酸（NAPVSIPQ），被认为是活性依赖性神经保护蛋白（ADNP）的ADNF-9样片段。NAP和SAL/ADNF-9的保护作用已被研究，特别是在体外。在NIH-NICHD使用产前腹膜内注射酒精和肽进行的体内研究已经证明，肽预防酒精诱导的胎儿死亡。我们实验室的体内研究使用液体饮食范例作为适度饮酒的模型，通过形态学分析证明了NAP和SAL/ADNF-9肽的神经保护作用。NAP和SAL/ADNF-9肽的神经保护作用的细胞机制仍然没有完全表征。在胎儿酒精暴露模型中，NAP和SAL/ADNF-9是否通过增殖或凋亡起作用尚不清楚。在我们和其他实验室进行的体外研究表明，这些肽可能通过预防细胞凋亡发挥作用。基于体外研究结果，我们假设NAP和SAL/ADNF-9肽通过凋亡调节诱导神经保护作用，对抗产前酒精暴露的损伤。由于NAP和SAL/ADNF-9对产前酒精暴露的影响的分子机制尚未阐明，我们的目的是在拟议的实验，以确定精确的时间组织的信号转导结果和描绘NAP和SAL/ADNF-9肽的神经保护途径。从拟议的实验中产生的数据将提供有关NAP和SAL/ADNF-9细胞内靶点的信息。这些数据将揭示大脑个体发育的机制，并为与产前酒精暴露相关的发育损伤的潜在治疗铺平道路。