Receptor Specific Retinoids Probes to Study the Brain Damage Caused byDevelopmental Alcohol Exposure

摘要 怀孕期间饮酒会对胎儿造成各种急性和长期的不良影响， 导致子代出现胎儿酒精谱系障碍(FASD)。特别是，发育中的大脑对 酒精中毒和认知功能障碍，如学习和记忆，可以在FASD中看到 病人。虽然许多因素可能涉及酒精对发育中的大脑的毒性，但维甲酸(RA) 在酒精中毒的过程中常常涉及到信号通路，因为RA(维生素的活性形式 A)通过核RA受体调节转录和翻译在 胚胎及其中枢神经系统的发育，酒精已被证明干扰维甲酸(与 维生素A)代谢。而精确控制RA在胚胎细胞群体中的分布似乎是 是必要的，而且中枢神经系统中RA的过量或枯竭已被证明会干扰大脑发育，酒精 通过几种机制干扰维甲酸的代谢，导致RA的激活或失活 信号通路。因此，RA信号通路可能成为开发治疗药物的靶点。 酒精中毒在大脑发育中的应用。这项翻译研究提案旨在确定 实验室合成的新型维甲酸衍生物(RA受体激动剂和拮抗剂)的给药 Bhaskar Das博士(PI，西奈山伊坎医学院)减轻产前或新生儿酒精诱导 急性神经变性以及神经发生、神经解剖和行为的长期异常， 在齐藤真理子博士(Nathan Kline Research Institute)的实验室中使用FASD的小鼠模型。这个 本项目的具体目标是：目标。1：从我们的先导分子中合成额外的新型维甲酸 完全表征了特异性和生物活性(Das博士的S小组；参见自然化学生物学2013 PMID： 23584676、《公共科学图书馆》2011年PMID：22125642和《PLOS One》2010年PMID：20368991)。然后，我们将迭代 合成更多化合物的过程，这些化合物更耐酶切，更有效， 更具受体特异性。在特定的目标2中，我们将确定RA受体激动剂或拮抗剂是否阻止 早期酒精诱导的细胞存活、神经发生、神经解剖和行为异常。酒精，与 或不含RA衍生物，将在妊娠第8天(GD8)(妊娠早期模型)注射到母猪或幼崽在 出生后第7天(P7)(晚期妊娠模型)，我们将评估RA衍生物是否减弱酒精诱导的 急性神经变性和神经发生的长期异常、GABA能细胞密度和 行为(运动活动和情景恐惧条件作用)。成功完成此翻译 研究计划将有助于确定为治疗FASD而开发的目标维甲酸衍生物。

ABSTRACT Alcohol intake during pregnancy causes wide varieties of acute and long-lasting adverse effects on fetuses, resulting in fetal alcohol spectrum disorders (FASD) in offspring. Especially, the developing brain is sensitive to alcohol toxicity, and impairments in cognitive functions, such as learning and memory, can be seen in FASD patients. While many factors may be involved in alcohol toxicity in the developing brain, the retinoic acid (RA) signaling pathway is often implicated in the process of alcohol toxicity, because RA (the active form of vitamin A) that regulates transcription and translation via nuclear RA receptors plays an important role in the development of embryos and their CNS, and alcohol has been shown to disturb retinoid (compounds related to vitamin A) metabolism. While precise control of RA distribution within embryonic cell populations seems to be necessary, and the excess or depletion of RA in the CNS has been shown to disturb brain development, alcohol interferes with retinoid metabolism by several mechanisms, resulting in activation or inactivation of the RA signaling pathway. Therefore, the RA signaling pathway may serve as a target for developing therapeutic applications in alcohol toxicity in the developing brain. This translational research proposal aims to determine if administration of novel retinoid derivatives (RA receptor agonists and antagonists) synthesized in the laboratory of Dr. Bhaskar Das (PI, Icahn School of Medicine at Mount Sinai) alleviates prenatal or neonatal alcohol-induced acute neurodegeneration as well as long-lasting abnormalities in neurogenesis, neuroanatomy, and behavior, using mouse models of FASD in the laboratory of Dr. Mariko Saito (Co-PI, Nathan Kline Research Institute). The specific aims of this project are: Aim. 1: To synthesize additional novel retinoids from our lead molecules that are fully characterized for specificity and bioactivity (Dr. Das’ s group; see Nature Chemical Biology 2013 PMID: 23584676, PLos One 2011 PMID:22125642 and PLos One 2010 PMID: 20368991). Then we will iterate the process to synthesize additional compounds, which are more resistant to protease cleavage, more potent, and more specific to receptors. In the specific Aim 2, we will determine if RA receptor agonists or antagonists prevent early alcohol-induced abnormalities in cell survival, neurogenesis, neuroanatomy and behaviors. Alcohol, with or without RA derivatives, will be injected into dams at gestational day 8 (GD8) (1st trimester model) or pups at postnatal day 7 (P7) (3rd trimester model), and we will assess whether RA derivatives attenuate alcohol-induced acute neurodegeneration and long-lasting abnormalities in neurogenesis, GABAergic cell densities, and behaviors (locomotor activity and contextual fear conditioning). Successful completion of this translational research program will help identify target retinoid derivatives to be developed for the treatment for FASD.