Molecular mechanism of ADNF and ADNP peptides in neuroprotection to alcohol

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识别酒精的特定作用的拮抗剂。反过来，这些研究调查了先前在体外和体内被证明参与神经保护的肽可能预防产前酒精暴露的影响。在这些肽中，9个氨基酸的活性片段（salrsipa）， SAL或ADNF-9，是模仿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。在体外研究了NAP和SAL/ADNF-9的保护作用。NIH-NICHD通过产前腹腔注射酒精和多肽进行的体内研究表明，多肽可以预防酒精引起的胎儿死亡。我们实验室的体内研究使用液体饮食范式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尚不完全清楚。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起作用。基于体外实验结果，我们假设NAP和SAL/ADNF-9肽通过凋亡调控诱导胎儿酒精暴露损伤的神经保护作用。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，我们在提出的实验中旨在确定信号转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。实验产生的数据将提供有关NAP和SAL/ADNF-9细胞内靶标的信息。这一数据将阐明控制大脑个体发生的机制，并将为潜在的治疗方法铺平道路，以对抗与产前酒精暴露相关的发育损害。

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.