权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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）包括一系列由慢性酒精暴露引起的疾病