Prostaglandins and Cerebellum Development

前列腺素和小脑发育

基本信息

批准号：
7979917
负责人：
MARGARET M. MCCARTHY
金额：
$ 37.5万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7979917
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 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，其根源在于发育、遗传和环境。了解环境影响如何与特定发育窗口期间的遗传倾向相结合以创建敏感期，是发现这些复杂疾病的病因和潜在治疗方法的关键。该提案探讨了特定的环境影响、炎症和治疗药物如何选择性地改变大脑发育并在不存在的情况下造成脆弱性。胎儿期或生命早期的炎症大大增加了患自闭症或精神分裂症的相对风险，但炎症带来这种风险的机制和敏感期仍不清楚。小脑的病理通常与这两种疾病相关，但尚未考虑炎症对该大脑区域的影响。性别也是一个主要风险因素，男性患自闭症或自闭症谱系障碍 (ASD) 的风险几乎是男性的四倍，而且精神分裂症发病较早，症状更严重。大脑中的许多性别差异是由发育性性腺激素暴露决定的。我们建议利用实验室大鼠探索一个新概念，即受限敏感期的炎症会导致前列腺素 E2 (PGE2) 过量，前列腺素 E2 是一种促炎分子，可刺激小脑内局部芳香酶活性和雌二醇合成。过量的雌二醇通过上调 GABA 合成来阻碍浦肯野神经元树突的生长。相反，接触非甾体抗炎药或对乙酰氨基酚等抗炎药物会产生相反的效果，导致茂盛的树突发芽。最终，小脑发育正常过程的破坏会导致青少年行为发生变化，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系统地探索一系列假设； SA#1) 前列腺素调节小脑浦肯野细胞树突发育的敏感期，SA#2) 前列腺素调节小脑浦肯野细胞树突发育的机制，SA#3) 内源性和内源性前列腺素的作用和机制外源性雌二醇对小脑浦肯野细胞发育的影响和 SA#4) 在敏感时期影响浦肯野细胞发育的操作是否会对被视为行为指标的行为产生影响与自闭症或精神分裂症相关的变化。这些实验产生的数据将强调以前意想不到的发育性神经精神疾病风险来源、炎症期间前列腺素升高和/或旨在阻止炎症的常用药物。公共卫生相关性：导致自闭症、自闭症谱系障碍和精神分裂症相对风险的环境变量之一是胎儿期或生命早期的炎症。小脑的病理常常与这些神经精神疾病相关。了解炎症和治疗炎症的药物如何影响发育中的小脑，将为了解这些心理健康疾病的起源提供重要的机制见解。