Autophagic Protection of Ethanol Neurotoxicity

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是精神发育迟滞的主要原因之一，因此是一个主要的公共卫生问题。发育中的中枢神经系统（CNS）对酒精特别敏感。发育中酒精暴露的最有害影响之一是中枢神经系统中神经元的永久性丧失。乙醇诱导神经元死亡的细胞/分子机制尚不清楚。在过去的十年中，线粒体损伤和氧化应激被认为在乙醇相关的CNS损伤的发病机制中起重要作用。然而，线粒体损伤并不能完全解释乙醇的神经毒性。乙醇对其他细胞器的影响很少受到关注，线粒体损伤和其他细胞器功能障碍之间的联系也知之甚少。这项资助计划试图填补这一空白，并研究乙醇对内质网（ER）和自噬之间相互作用的影响。ER应激在各种生理和病理条件下诱导，其中发生未折叠蛋白质的积累或ER Ca 2+稳态的破坏。自噬是一种参与细胞大分子和细胞器周转的溶酶体途径，在内质网应激期间被诱导以减轻细胞毒性。我们已经证明，乙醇诱导ER应激在发育中的神经元。我们推测，乙醇神经毒性部分是由诱导内质网应激和同时损害的保护性自噬通路。作为推论，我们提出，自噬途径的激活在乙醇暴露可以改善乙醇的细胞毒性;相反，自噬的抑制加剧了乙醇的影响。为了验证这一假设，我们将首先确定乙醇是否抑制内质网应激引发的自噬.接下来，我们将通过药理学或遗传学方法激活或抑制自噬途径，并确定自噬途径的调节是否改善或加剧乙醇细胞毒性。 我们的假设是新颖的，拟议的研究是有意义的，它将提供新的见解乙醇对内质网和溶酶体降解途径的影响。这将为减轻乙醇的细胞毒性提供一个潜在的途径。 公共卫生相关性：产前接触酒精会对发育中的大脑造成严重损害。胎儿酒精综合征是智力迟钝的主要原因。发育期酒精暴露的最有害影响之一是大脑中神经元的永久性丧失。然而，酒精如何杀死未成熟的神经元仍不清楚。内质网（ER）是一种处理蛋白质和储存钙的细胞器。我们已经证明，乙醇导致ER损伤。自噬是一种参与细胞大分子和细胞器更新的溶酶体途径，在ER损伤过程中被诱导以减轻细胞毒性。我们的研究将测试一个新的假设，即酒精神经毒性部分是由内质网损伤和同时损害的保护性自噬途径。我们的研究将提供新的洞察酒精对ER和溶酶体降解途径的影响。它可能提供一种新的治疗途径。

DESCRIPTION (provided by applicant): Fetal alcohol spectrum disorder (FASD) is one of the leading causes of mental retardation, and thus is a major public health concern. The developing central nervous system (CNS) is particularly sensitive to alcohol. One of the most deleterious effects of developmental alcohol exposure is the permanent loss of neurons in the CNS. The cellular/molecular mechanisms underlying ethanol-induced neuronal death remain unclear. During the last decade, mitochondria damage and oxidative stress have been believed to play an important role in the pathogenesis of ethanol-associated CNS injury. However, mitochondria damage does not fully explain ethanol neurotoxicity. The effects of ethanol on other cellular organelles receive little attention, and the connection between mitochondria damage and other organelle dysfunction is poorly understood. This grant proposal attempts to fill this gap and investigate the effect of ethanol on the interaction between the endoplasmic reticulum (ER) and autophagy. ER stress is induced in various physiological and pathological conditions where the accumulation of unfolded proteins or disruption of ER Ca2+ homeostasis occurs. Autophagy, a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, is induced to alleviate cytotoxicity during ER stress. We have demonstrated that ethanol induces ER stress in developing neurons. We hypothesize that ethanol neurotoxicity is partially caused by the induction of ER stress and the simultaneous impairment of the protective autophagic pathway. As a corollary, we propose that activation of autophagy pathways during ethanol exposure can ameliorate ethanol cytotoxicity; contrarily, inhibition of autophagy exacerbates the effect of ethanol. To test this hypothesis, we will first determine whether ethanol inhibits ER stress- triggered autophagy. Next, we will activate or inhibit the autophagic pathway by pharmacological or genetic approaches and determine whether the modulation of autophagic pathways ameliorates or exacerbates ethanol cytotoxicity. Our hypothesis is novel and the proposed study is significant; it will offer new insight into the effect of ethanol on the endoplasmic reticulum and lysosomal degradation pathways. It will provide a potential avenue for alleviating ethanol cytotoxicity. PUBLIC HEALTH RELEVANCE: Prenatal exposure to alcohol causes profound damages to the developing brain. Fetal alcohol syndrome is the leading cause of mental retardation. One of the most deleterious effects of developmental alcohol exposure is the permanent loss of neurons in the brain. However, it remains unclear how alcohol kills immature neurons. The endoplasmic reticulum (ER) is an organelle that processes proteins and stores calcium. We have shown that ethanol causes ER injury. Autophagy, a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, is induced to alleviate cytotoxicity during ER damage. Our study will test a novel hypothesis that alcohol neurotoxicity is partially caused by ER damage and simultaneous impairment of the protective autophagic pathway. Our study will offer novel insight into the effect of alcohol on the ER and lysosomal degradation pathways. It may provide a new therapeutic avenue.