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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

基本信息

批准号：
7491649
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
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7491649
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

项目摘要

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。先前的研究主要集中在识别酒精特定作用的拮抗剂。反过来，这些研究也调查了用肽预防产前酒精暴露效应的可能性，这些肽先前已被证明参与体外和体内的神经保护。在这些肽中，九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 的保护作用已在体外进行了特别研究。 NIH-NICHD 使用产前腹腔注射酒精和肽进行的体内研究表明，这些肽可以防止酒精引起的胎儿死亡。我们实验室的体内研究使用流质饮食范例作为适量饮酒的模型，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尚未完全表征。目前尚不清楚 NAP 和 SAL/ADNF-9 在胎儿酒精暴露模型中是否通过增殖或凋亡发挥作用。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 肽通过细胞凋亡调节诱导神经保护，抵抗产前酒精暴露的损伤。由于 NAP 和 SAL/ADNF-9 对抗产前酒精暴露影响的分子机制尚未阐明，我们的目标是在拟议的实验中确定信号传导结果的精确时间组织，并描绘 NAP 和 SAL/ADNF-9 肽的神经保护途径。拟议实验生成的数据将提供有关 NAP 和 SAL/ADNF-9 细胞内靶标的信息。这些数据将揭示控制大脑个体发育的机制，并为针对与产前酒精暴露相关的发育损伤的潜在治疗方法铺平道路。