Epigenetic Mechanisms in the Perpetuation of Anorexia Nervosa-like Behavior

神经性厌食症样行为持续的表观遗传机制

基本信息

批准号：
8281794
负责人：
KELLIE L. K. TAMASHIRO
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8281794
关键词：
Acute Adolescence Adolescent Adult Animal Model Animals Anorexia Anorexia Nervosa Anxiety Behavior Behavior Disorders Behavioral Biological Biological Assay Biology Body Image Body Weight decreased Brain Brain region Characteristics Clinical Coupled CpG Islands DNA Methylation Data Development Diet Disease Eating Eating Disorders Emaciation Epigenetic Process Exercise Family Study Fatty acid glycerol esters Female Food Food Access Food Aversion Fright Gene Expression Genes Genetic Genome Glucocorticoids Homeostasis Human Hyperactive behavior Individual Learning Life Experience Long-Term Effects Malnutrition Mediating Mental disorders Methylation Modeling Mood Disorders National Institute of Mental Health Neurobiology Nutritional Patients Personality Personality Traits Physical activity Play Predisposition Prevalence Probability Promoter Regions Protocols documentation Psychosocial Influences Rattus Recovery Relapse Relative (related person)Reporting Resistance Rewards Risk Rodent Role Running Schedule Secondary to Starvation Stress Testing Thinness Time Twin Studies Weight Weight Gain base biological adaptation to stress critical developmental period critical period effective therapy excessive exercise experience food restriction genetic linkage genome-wide male mortality neural circuit neurobiological mechanism novel relating to nervous system research study restraint reward processing treatment strategy

Acute Adolescence Adolescent Adult Animal Model Animals Anorexia Anorexia Nervosa Anxiety Behavior Behavior Disorders Behavioral Biological Biological Assay Biology Body Image Body Weight decreased Brain Brain region Characteristics Clinical Coupled CpG Islands DNA Methylation Data Development Diet Disease Eating Eating Disorders Emaciation Epigenetic Process Exercise Family Study Fatty acid glycerol esters Female Food Food Access Food Aversion Fright Gene Expression Genes Genetic Genome Glucocorticoids Homeostasis Human Hyperactive behavior Individual Learning Life Experience Long-Term Effects Malnutrition Mediating Mental disorders Methylation Modeling Mood Disorders National Institute of Mental Health Neurobiology Nutritional Patients Personality Personality Traits Physical activity Play Predisposition Prevalence Probability Promoter Regions Protocols documentation Psychosocial Influences Rattus Recovery Relapse Relative (related person)Reporting Resistance Rewards Risk Rodent Role Running Schedule Secondary to Starvation Stress Testing Thinness Time Twin Studies Weight Weight Gain base biological adaptation to stress critical developmental period critical period effective therapy excessive exercise experience food restriction genetic linkage genome-wide male mortality neural circuit neurobiological mechanism novel relating to nervous system research study restraint reward processing treatment strategy

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项目摘要

DESCRIPTION (provided by applicant: Anorexia nervosa (AN) is a severe eating disorder with a very high relapse rate and mortality. In addition to body image distortion, self-imposed eating restraint, serious weight loss, and fear of "fat"/weight gain, up to 80% of patients with AN are engaged in high levels of physical activity during the development of their eating disorders. One animal model that mimics several aspects of AN, including hyperactivity and voluntary reductions on food intake, is "activity-based anorexia" (ABA). In this rat model, animals have free access to running wheels and 1 h restricted access to food each day. During this free running and restricted food access schedule, rats become hyperactive and anorexic, and lose a significant amount of weight, and will eventually die of starvation if the scheduled is not terminated. Experience with ABA during adolescence increases anxiety-like behavior and facilitates food aversion learning in adulthood. These data suggest that adolescent experience with hyperactivity and food restriction has long- term behavioral consequences. The neurobiological mechanisms proposed involve brain regions that mediate stress and reward processes. We hypothesize that experience with AN-like behavior during adolescence could result in persistent epigenetic alterations in the brain that increase susceptibility to relapse of disordered behavior and contributes to the perpetuation of AN in patients. Combining the ABA animal model with a novel genome-wide epigenetic platform, Comprehensive High-throughput Array for Relative Methylation ("CHARM"), this proposal aims to determine the acute and long term consequences of ABA experience during adolescence on DNA methylation and gene expression in brain regions important to stress and reward. The experiments in this proposal will provide new information about the epigenetic consequences of adolescent experience with AN-like behavior and may facilitate development of more effective clinical therapy for AN and related eating disorders. PUBLIC HEALTH RELEVANCE: Anorexia Nervosa (AN) is a severe eating disorder for which there are no effective treatments. Adolescence is a critical period during development when many biological changes occur and can persist through adulthood. We will use an animal model of AN, "activity-based anorexia" (ABA), to determine the short- and long-term consequences of adolescent experience with ABA on epigenetic marks in the brain. The results of these experiments will provide new information about how AN develops and how the disease is maintained to identify novel targets in the brain that may be used to develop more effective treatment strategies for AN and related eating disorders.

描述（由申请人提供：神经性厌食症（AN）是一种严重的饮食失调症，复发率和死亡率很高。除了身体形象扭曲，自我施加的饮食约束，严重的体重减轻以及对“脂肪”/体重增加的恐惧，多达80％的患者患有80％的患者在饮食失调的发展过程中，从事高水平的体育活动。一个模仿AN的几个方面的动物模型，包括对食物摄入的多动症和自愿减少，是“基于活动的厌食症”（ABA）。在这种大鼠模型中，动物可以自由进入跑步车轮，每天有1小时的限制进入食物。在此免费的跑步和限制的食物获取时间表中，大鼠变得过度活跃和厌食，并减轻体重，如果计划未终止，最终将死于饥饿。青春期ABA的经验增加了焦虑般的行为，并促进了成年后的食物厌恶学习。这些数据表明，过度活跃和食物限制的青少年经验具有长期的行为后果。提出的神经生物学机制涉及介导压力和奖励过程的大脑区域。我们假设在青春期中具有类似AN样行为的经验可能会导致大脑中持续的表观遗传改变，从而增加了对复发的敏感性行为无序，并导致患者的持续性。该提案将ABA动物模型与全基因组的表观遗传平台相结合，用于相对甲基化的全面高通量阵列（“ Charm”），旨在确定ABA经验在青少年期间对DNA甲基化和脑区域中对压力和奖励重要的DNA甲基化和基因表达的急性和长期后果。该提案中的实验将提供有关青少年经验具有类似AN样行为的表观遗传后果的新信息，并可能促进为AN和相关饮食失调的更有效的临床治疗开发。公共卫生相关性：神经性厌食症（AN）是一种严重的饮食失调症，没有有效的治疗方法。青春期是许多生物学变化发生并可以在成年期间持续存在的关键时期。我们将使用“基于活动的厌食症”（ABA）的动物模型来确定ABA青少年经验对大脑表观遗传标记的短期和长期后果。这些实验的结果将提供有关如何发展以及如何维持疾病以识别大脑中新型靶标的新信息，这些靶标可用于制定针对AN和相关饮食失调的更有效的治疗策略。