Role of exosomes in ethanol-induced neurotoxicity

胎儿酒精谱系障碍(FASD)包括一系列由慢性酒精暴露引起的疾病 在怀孕期间。据记录，在美国出生的儿童中，约有2%至5%患有 FASD。临床研究表明，患有FASD的儿童和成人经常表现出对压力的高反应性 而且容易患精神障碍，特别是情绪障碍。这些情绪的神经生物学 这种干扰还不是很清楚，但利用胎儿酒精暴露的动物模型进行的研究表明 实验室大鼠和小鼠出生前或出生后早期的酒精暴露会扰乱下丘脑- 垂体-肾上腺轴的功能及其对压力的生理反应，并促进焦虑样行为。 产前酒精暴露和出生后酒精暴露均可诱导下丘脑阿片黑素原皮质素 神经元死亡和降低前阿片黑素皮质素及其多肽产物β-内啡肽以及β- 内啡肽对下丘脑-垂体-肾上腺轴功能的抑制调控。补充β- 通过神经元移植的内啡肽神经元预防胎儿酒精应激和行为问题 裸露 动物，表明β-内啡肽缺乏是压力和行为的重要贡献者 这些动物的异常。β-内啡肽神经元在损伤后发生细胞凋亡的机制 胎儿酒精暴露还没有被很好地理解。有几个临床前和临床证据表明 提示小胶质细胞是中枢神经系统中的一种免疫细胞，在调节 酒精引起的神经元损伤。最近的研究表明，炎性细胞因子可以在 与来自小胶质细胞的称为外体的细胞外小泡联系在一起。这些外显体由 由来自宿主细胞的脂双层、跨膜蛋白和胞浆成分组成。然而， 小胶质细胞外切体在酒精诱导的神经毒性中的作用还没有得到很好的研究。在这项提案中，我们 建议确定小胶质细胞是否使用外切体诱导乙醇诱导的β-内啡肽神经元死亡和 应力轴函数。我们还建议使用蛋白质组和基因组测量来确定乙醇 出生后治疗可提高小鼠脑内趋化因子、补体和microRNAs水平 小胶质细胞外切体。此外，我们还建议鉴定具有细胞凋亡作用的外体生物分子。 在β-内啡肽神经元上。总而言之，这些研究应该确定产前乙醇如何改变 外切体中的蛋白质和基因诱导可能导致应激轴的β-内啡肽神经元凋亡 反应过度和焦虑行为增加。此外，拟议的研究可能会确定一部小说 预防FASD患者出现的一些神经问题的治疗方法。

Fetal alcohol spectrum disorders (FASD) include a range of maladies caused by chronic alcohol exposure during pregnancy. It is documented that approximately 2% to 5% of children born in the United States have FASD. Clinical studies have shown children and adults with FASD often show hyperresponsiveness to stress and are vulnerable to psychiatric disorders, particularly mood disorders. The neurobiology of these emotional disturbances are not well understood, but studies utilizing animal models of fetal alcohol exposure have shown that prenatal or early-postnatal ethanol exposure in laboratory rats and mice disrupts the hypothalamic- pituitary-adrenal axis function and its physiological response to stress and promotes anxiety-like behaviors. Both prenatal ethanol exposure and postnatal ethanol exposure induce hypothalamic proopiomelanocortin neuronal death and reduce levels of proopiomelanocortin and its peptide product β-endorphin, as well as the β- endorphin peptide's inhibitory control of the hypothalamic-pituitary-adrenal axis function. Replenishment of β- endorphin neurons via neuronal transplantation prevents stress and behavioral problems in fetal alcohol- exposed animals, indicating that β-endorphin deficiency is a significant contributor to the stress and behavioral abnormalities in these animals. The mechanism by which β-endorphin neurons experience apoptosis following fetal alcohol exposure is not well understood. There are several preclinical and clinical evidences that suggest microglia, one of the immune cells in the central nervous system, play a major role in the regulation of alcohol-induced neuronal damage. Recent studies show that inflammatory cytokines can be released in association with small extracellular vesicles, called exosomes, from microglia. These exosomes are comprised of a lipid bilayer, transmembrane proteins, and cytosolic components derived from their host cells. However, the role of microglial exosomes in alcohol-induced neurotoxicity has not been well studied. In this proposal, we propose to determine if microglia use exosomes to induce ethanol-induced β-endorphin neuronal death and stress axis functions. We also propose to use proteomic and genomic measurements to identify if ethanol treatment during the postnatal period increases levels of chemokines, complements, and microRNAs in microglial exosomes. Additionally, we propose to identify the exosome biomolecules that have apoptotic effects on β-endorphin neurons. Together these studies should establish how prenatal ethanol modifies contents of proteins and genes within exosomes to induce β-endorphin neuronal apoptosis that may lead to stress axis hyperresponsiveness and increased anxiety behavior. Additionally, the proposed studies may identify a novel therapeutic approach to prevent some of the neurological problems that occur in FASD patients.