Role of exosomes in ethanol-induced neurotoxicity

胎儿酒精谱系障碍（FASD）包括一系列由长期酒精暴露引起的疾病 孕期据记载，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 并且易患精神疾病，特别是情绪障碍。这些情绪的神经生物学 干扰还没有得到很好的理解，但利用胎儿酒精暴露的动物模型的研究表明， 实验室大鼠和小鼠在出生前或出生后早期接触乙醇会破坏下丘脑- 垂体-肾上腺轴功能及其对压力的生理反应，并促进焦虑样行为。 出生前和出生后乙醇暴露均可诱导下丘脑阿黑皮素原的产生 神经元死亡和阿黑皮素原及其肽产物β-内啡肽水平降低，以及β- 内啡肽对下丘脑-垂体-肾上腺轴功能的抑制性调控。补充β- 内啡肽神经元通过神经元移植防止胎儿酒精的压力和行为问题， 暴露 动物，表明β-内啡肽缺乏是一个显着的贡献者的压力和行为 这些动物的异常。β-内啡肽诱导神经元凋亡的机制 胎儿酒精暴露还不是很清楚。有几个临床前和临床证据表明， 提示小胶质细胞，中枢神经系统中的免疫细胞之一，在调节 酒精引起的神经元损伤最近的研究表明，炎症细胞因子可以释放， 与来自小胶质细胞的称为外泌体的小细胞外囊泡相关联。这些外泌体由 脂质双层、跨膜蛋白和来自其宿主细胞的胞质组分。然而，在这方面， 小胶质细胞外泌体在酒精诱导的神经毒性中的作用尚未得到充分研究。在本提案中，我们 建议确定小胶质细胞是否使用外来体诱导乙醇诱导的β-内啡肽神经元死亡， 应力轴函数。我们还建议使用蛋白质组学和基因组学测量来确定乙醇是否 在出生后阶段的治疗增加了趋化因子，补体和microRNA的水平， 小胶质细胞外泌体。此外，我们建议鉴定具有凋亡作用的外泌体生物分子， 对β-内啡肽神经元的影响总之，这些研究应该建立产前乙醇如何改变 外泌体内的蛋白质和基因诱导β-内啡肽神经元凋亡，可能导致应激轴 高反应性和焦虑行为增加。此外，拟议的研究可能会发现一种新的 治疗方法，以防止发生在FASD患者的一些神经问题。

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.