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Role of exosomes in ethanol-induced neurotoxicity

外泌体在乙醇诱导的神经毒性中的作用

基本信息

批准号：
10266778
负责人：
DIPAK KUMAR SARKAR
金额：
$ 35.1万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10266778
关键词：
Adult Adverse effects Alcohol-Induced Neurotoxicity Alcohols Animal Model Animals Anxiety Apoptosis Apoptotic Astrocytes Behavior Behavioral Biogenesis Blood Body Fluids Brain Cell Death Cell Maturation Cell membrane Cells Cerebrospinal Fluid Cessation of life Child Chronic Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Communication Complement Corticosterone Corticotropin Defect Emotional Disturbance Endothelial Cells Enzyme-Linked Immunosorbent Assay Ethanol Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Genes Genomics Growth Homeostasis Hormonal Human Human Milk Hypothalamic structure Immune In Situ In Vitro Individual Infant formula Inflammatory Integral Membrane Protein Laboratory Rat Laboratory mice Lead Learning Disabilities Lipid Bilayers Lipids Measurement Measures Membrane Lipids Mental disorders MicroRNAs Microglia Modeling Mood Disorders Names Neuraxis Neurobiology Neuroglia Neurologic Neurons Newborn Infant Oligodendroglia Oligonucleotides Oxidative Stress POMC gene Pathway interactions Patients Peptides Physiological Play Population Pregnancy Prevalence Pro-Opiomelanocortin Problem behavior Production Property Proteins Proteomics RNA Rattus Regulation Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Series Signal Pathway Signal Transduction Stress Structure Techniques Testing Third Pregnancy Trimester Tissues Transplantation United States Urine Vesicle Western Blotting alcohol exposure anxiety-like behavior base beta-Endorphin biological adaptation to stress cell behavior cell type chemokine cytokine dietary control exosome experience extracellular vesicles fetal genomic data hypothalamic-pituitary-adrenal axis immune function in vivo knock-down microvesicles monocyte nerve stem cell neuron apoptosis neuron loss neurotoxicity neurotransmission novel novel therapeutic intervention particle postnatal postnatal period pre-clinical prenatal prevent response socioeconomics stem stem cell growth therapeutically effective uptake

项目摘要

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.

胎儿酒精谱系障碍 (FASD) 包括一系列因长期接触酒精而引起的疾病怀孕期间。据记录，在美国出生的儿童中大约有 2% 至 5% 患有胎儿酒精谱系障碍。临床研究表明，患有 FASD 的儿童和成人经常表现出对压力的过度反应并且容易患精神疾病，特别是情绪障碍。这些情绪的神经生物学这种干扰尚不清楚，但利用胎儿酒精暴露动物模型的研究表明实验室大鼠和小鼠的产前或产后早期乙醇暴露会扰乱下丘脑垂体-肾上腺轴功能及其对压力的生理反应，并促进焦虑样行为。产前乙醇暴露和产后乙醇暴露都会诱导下丘脑阿片黑皮质素原神经元死亡并降低阿片黑皮质素原及其肽产物 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控制。补充β- 通过神经元移植的内啡肽神经元可以预防胎儿酒精中的压力和行为问题裸露动物，表明β-内啡肽缺乏是导致压力和行为的重要因素这些动物的异常。 β-内啡肽神经元凋亡的机制胎儿酒精暴露尚不清楚。有多项临床前和临床证据表明表明小胶质细胞是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，炎症细胞因子可以在与来自小胶质细胞的小细胞外囊泡（称为外泌体）相关。这些外泌体包含脂质双层、跨膜蛋白和源自宿主细胞的胞质成分。然而，小胶质细胞外泌体在酒精引起的神经毒性中的作用尚未得到充分研究。在这个提案中，我们提议确定小胶质细胞是否使用外泌体诱导乙醇诱导的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学和基因组测量来确定乙醇是否产后治疗会增加趋化因子、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 β-内啡肽神经元。这些研究共同应确定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，可能导致应激轴反应过度和焦虑行为增加。此外，拟议的研究可能会确定一种新颖的预防 FASD 患者出现的一些神经系统问题的治疗方法。