Prostaglandins and Cerebellum Development

前列腺素和小脑发育

基本信息

批准号：
8242868
负责人：
MARGARET M. MCCARTHY
金额：
$ 37.13万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-23 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242868
关键词：
Acetaminophen Adolescent Agonist Anti-Inflammatory Agents Anti-inflammatory Anxiety Aromatase Aromatase Inhibitors Autistic Disorder Behavior Behavioral Brain Brain region Cerebellum Complex Cyclooxygenase Inhibitors Data Dendrites Development Dinoprostone Disease Drug Exposure Environment Estradiol Estradiol Receptors Estrogen Receptors Etiology Exposure to GABA Agonists Gender Genetic Genetic Predisposition to Disease Gonadal Hormones Growth Inflammation Laboratory Rat Life Mental disorders Modeling Neurons Non-Steroidal Anti-Inflammatory Agents Pathology Pharmaceutical Preparations Physiologic pulse Play Production Prostaglandin Inhibition Prostaglandin Production Prostaglandins Purkinje Cells Relative Risks Risk Risk Factors Schizophrenia Secondary to Series Sex Characteristics Social Behavior Source Sprague-Dawley Rats Steroid biosynthesis Symptoms Therapeutic Time Trees autism spectrum disorder cell growth design early onset fetal gamma-Aminobutyric Acid indexing inhibitor/antagonist insight male neuron development neuropsychiatry novel postnatal prevent public health relevance research study social somatosensory

项目摘要

DESCRIPTION (provided by applicant): Autism Spectrum Disorder (ASD) and Schizophrenia are neuropsychiatric diseases with origins in development, genetics and the environment. Understanding how environmental influences converge with genetic predispositions during specific developmental windows to create a sensitive period is the key to discovering the etiology of and potential therapeutic treatments for these complex disorders. This proposal explores how a specific environmental influence, inflammation and the medications that treat it, can selectively alter brain development and create vulnerability where none existed. Inflammation during fetal or early life substantially increases the relative risk of developing either Autism or Schizophrenia, but the mechanism(s) and sensitive periods by which inflammation confers this risk remain unknown. Pathologies of the cerebellum are frequently associated with both disorders but an effect of inflammation on this brain region has not been considered. Gender is also a major risk factor, with males at almost four times the risk of Autism or (ASD) and an earlier onset of Schizophrenia with more severe symptoms. Many sex differences in the brain are determined by developmental gonadal hormone exposure. Using the laboratory rat, we propose to explore the novel concept that inflammation during a restricted sensitive period leads to excess prostaglandin E2 (PGE2), a proinflammatory molecule that stimulates aromatase activity and estradiol synthesis locally within the cerebellum. Excessive estradiol stunts the outgrowth of Purkinje neuron dendrites by up regulating GABA synthesis. Conversely, exposure to anti-inflammatory medications such as NSAIDs or acetominophen, has the opposite effect, causing exuberant dendritic sprouting. Ultimately, disruption of the normal course of cerebellar development produces changes in juvenile behaviors such as social play, anxiety and somatosensory sensitivity. Four specific aims will systematically explore a series of hypotheses by determining; SA#1) the sensitive period for prostaglandin modulation of cerebellar Purkinje cell dendritic development, SA#2) the mechanism(s) of prostaglandin modulation of cerebellar Purkinje cell dendritic development, SA#3) the effects and mechanism(s) of endogenous and exogenous estradiol on cerebellar Purkinje cell development and SA#4) whether manipulations that impact Purkinje cell development during a sensitive period have consequences for behaviors deemed indicators of behavioral changes associated with autism or schizophrenia. The data generated by these experiments will highlight a previously unexpected source of risk for developmental neuropsychiatric disease, prostaglandins elevated during inflammation and/or the frequently used medications designed to block inflammation. PUBLIC HEALTH RELEVANCE: Among the environmental variables contributing to the relative risk of Autism, Autism Spectrum Disorder and Schizophrenia is inflammation during fetal or early life. Pathologies of the cerebellum are frequently associated with these neuropsychiatric disorders. Understanding how inflammation and the medications taken to treat it impact on the developing cerebellum will provide important mechanistic insight into the origins of these disorders of mental health.

描述（由申请人提供）：自闭症谱系障碍（ASD）和精神分裂症是神经精神疾病，起源于发育，遗传学和环境。了解环境在特定的发育窗口中如何融合遗传倾向以创建敏感时期，这是发现这些复杂疾病的病因和潜在治疗治疗的关键。该建议探讨了特定的环境影响，炎症和治疗它的药物如何有选择地改变大脑发育并在不存在的情况下造成脆弱性。胎儿或早期生命期间的炎症显着增加了发展自闭症或精神分裂症的相对风险，但是炎症赋予这种风险的机制和敏感时期的机制和敏感时期仍然未知。小脑的病理经常与这两种疾病有关，但尚未考虑炎症对该大脑区域的影响。性别也是一个主要的危险因素，男性的身高几乎是自闭症或（ASD）的四倍，并且具有更严重症状的精神分裂症。大脑中的许多性别差异取决于发育性性腺激素暴露。使用实验室大鼠，我们建议探索一个新的概念，即在受限敏感时期内的炎症会导致前列腺素E2（PGE2）过多，这是一种促炎分子，促进芳香酶活性和雌二醇合成在小脑内部。雌二醇过多的特技通过调节GABA合成，从而使Purkinje神经元树突的生长产生。相反，暴露于NSAIDS或乙酰氨基酚等抗炎药物具有相反的作用，从而导致旺盛的树突发芽。最终，小脑发展过程的破坏会导致少年行为的变化，例如社交游戏，焦虑和体感敏感性。四个具体目标将通过确定来系统地探索一系列假设。 SA＃1）小脑Purkinje细胞树突开发的前列腺素调节的敏感时期，SA＃2）小脑Purkinje细胞树突状发展的前列腺素调节的机制，SA＃3），SA＃3）在敏感时期，浦肯野细胞的发展对被认为与自闭症或精神分裂症相关的行为变化的行为产生了影响。这些实验产生的数据将突出以前出乎意料的发育神经精神疾病的风险，炎症期间升高的前列腺素和/或旨在阻止炎症的常用药物。公共卫生相关性：在导致自闭症相对风险的环境变量中，自闭症谱系障碍和精神分裂症是胎儿或早期生命期间的炎症。小脑的病理经常与这些神经精神疾病有关。了解炎症和治疗IT的药物如何影响发育中的小脑，将为这些心理健康疾病的起源提供重要的机械洞察力。