Protective effects of ovarian hormones: sex-specific differences in tlr4 expression after adolescent alcohol

卵巢激素的保护作用：青少年饮酒后 tlr4 表达的性别特异性差异

基本信息

批准号：
10204926
负责人：
Andrea Silva-Gotay
金额：
$ 4万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204926
关键词：
Adolescence Adolescent Adolescent Development Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Animal Model Antiinflammatory Effect Astrocytes Automobile Driving Award Behavior Behavioral Biological Assay Biological Process Brain Cell Density Cell Separation Cells Coupled Data Development Drug Addiction Elements Epigenetic Process Female Fiber Gene Expression Genes Goals Gonadal Hormones Hormonal Impaired cognition Inflammation Inflammation Mediators Inflammatory Knowledge Life Measurable Mediating Messenger RNA Microglia Microscopy Molecular Myelin Neurodegenerative Disorders Neuroglia Neuroimmune Neuroimmune system Ovarian hormone Pathway interactions Phase Population Prefrontal Cortex Prevention Primary Cell Cultures Procedures Process Proteins Rattus Research Research Project Grants Rodent Model Role Sex Differences TLR4 gene Techniques Testing Therapeutic Therapeutic Intervention Toll-like receptors Training Transgenic Animals Up-Regulation Work adolescent alcohol exposure adolescent alcohol treatment alcohol abuse therapy alcohol exposure alcohol intervention alcohol sensitivity alcohol use disorder base binge drinking cell type cognitive function density disorder risk drinking early adolescence early onset insight lifetime risk male neuroadaptation neuroinflammation post-doctoral training pre-doctoral protective effect receptor response targeted treatment transcriptome sequencing underage drinking

项目摘要

PROJECT SUMMARY/ABSTRACT Early onset of alcohol drinking is associated with an increased lifetime risk of alcohol use disorder (AUD) and impairment of cognitive functions dependent on the prefrontal cortex (Jennison, 2004; Townshend and Duka, 2005). Understanding how alcohol impacts the developing adolescent brain can help us identify molecular and cellular pathways to target for therapeutic intervention. Our lab has shown that just two weeks of voluntary alcohol drinking in early adolescence (during pubertal maturation) leads to reduced myelinated fiber density in the prefrontal cortex in males (Vargas et al., 2014), without measurable changes in female rats (unpublished). This sex difference may reflect differential upregulation of toll-like receptor 4 (TLR4), as this receptor has been shown to orchestrate a neuroinflammatory response (Blanco et al., 2010) and mediate myelin damage after heavy or prolonged alcohol exposure (Alfonso-Loeches et al., 2012). In support of this hypothesis, my dissertation research has confirmed that alcohol drinking upregulates TLR4 mRNA in the prefrontal cortex of male, but not female adolescent rats (Aim 1). Gonadal hormones have been shown to have neuroprotective and anti-inflammatory effects (Vegeto et al., 2003), however, their role in alcohol-mediated disruptions, like upregulation of toll-like receptors, remains unknown. Therefore, in the F99 predoctoral phase of this proposal I will test the role of circulating gonadal hormones in protecting females against these effects and identify the glial population involved. After I am done with my dissertation, my goal for the K00 phase is to study how the neuroimmune system adapts after alcohol exposure during adolescence, and how these neuroadaptations may contribute to alcohol abuse and alcohol use disorder later in life. Specifically, I will use RNAseq, transgenic animal models, primary cell cultures, and ChIP, along with mRNA and protein assays learned in the F99 phase, to answer how epigenetic changes induced by alcohol, especially those targeting neuroinflammatory genes, contribute to changes in biological function of different cell types and how this in turn regulates behavior. My ultimate goal for this research is to gain insight into the epigenetic targets of alcohol, which will help identify potential therapeutics for drug addiction and neurodegenerative disorders.

项目摘要/摘要早期饮酒的发作与终身患者饮酒障碍的风险增加有关（AUD）和认知功能的损害取决于前额叶皮层（Jennison，2004年； Townshend和Duka， 2005）。了解酒精如何影响发展中的青少年大脑可以帮助我们识别分子和靶向治疗干预靶向的细胞途径。我们的实验室表明，只有两个星期的自愿青春期早期饮酒（在青春期成熟期间）导致骨髓纤维密度降低男性的前额叶皮质（Vargas等，2014），没有雌性大鼠的可测量变化（未发表）。这种性别差异可能反映了Toll样受体4（TLR4）的差异上调，因为该受体已经是展示了用于编排神经炎症反应（Blanco等，2010），并介导髓磷脂损伤大量或长时间的酒精暴露（Alfonso-Loeches等，2012）。为了支持这一假设，我论文研究已经证实，酒精饮酒会在前额叶皮层中上调TLR4 mRNA 男性，但不是女性青春期大鼠（AIM 1）。性腺激素已被证明具有神经保护作用和抗炎作用（Vageto等，2003），它们在酒精介导的干扰中的作用，例如 Toll样受体的上调仍然未知。因此，在该提案的F99前阶段i 将测试循环性腺激素在保护女性免受这些作用中的作用，并确定涉及神经胶质。完成论文后，我的K00阶段目标是研究青春期酒精暴露后的神经免疫性系统适应于这些神经适应在以后的生活中可能会导致滥用酒精和饮酒障碍。具体来说，我将使用rnaseq，转基因动物模型，原代细胞培养物和芯片，以及mRNA和蛋白质分析 f99阶段，回答酒精引起的表观遗传变化，尤其是那些靶向的变化神经炎症基因，有助于不同细胞类型的生物学功能的变化，以及如何依次改变调节行为。这项研究的最终目标是深入了解酒精的表观遗传目标，这将有助于确定药物成瘾和神经退行性疾病的潜在疗法。