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The epigenetic basis of stress reacitvity: Implications for drug-exposed infants

应激反应性的表观遗传基础：对药物暴露婴儿的影响

基本信息

批准号：
9544136
负责人：
Liz D Conradt
金额：
$ 14.89万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9544136
关键词：
Affect Animals Area Basic Behavioral Science Basic Science Behavior Behavior Therapy Behavioral Bioinformatics Biological Candidate Disease Gene Child Development Child Rearing Clinical DNA Methylation Data Development Development Plans Developmental Process Diabetes Mellitus Disease Disease susceptibility Drug Exposure Early Intervention Environment Epidemiologist Epigenetic Process Exhibits Foxes Future Gene Expression Genes Genome Glucocorticoid Receptor Goals Health Heart Diseases Hippocampus (Brain)Human Individual Infant Intervention Studies K-Series Research Career Programs Knowledge Laboratories Lead Life Life Experience Link Literature Mediating Medical Mental disorders Mentors Mentorship Methods Methylation Modeling Molecular Morbidity - disease rate NR3C1 gene Neurosecretory Systems Obesity Phenotype Physiological Physiology Population Predisposition Problem behavior Process Psychologist Public Health Receptor Gene Research Research Personnel Rodent Rodent Model Role S Phase Scientist Series Shapes Signal Transduction Stress System Temperament Time Tissues Training Translating Variant Work base behavioral construct biobehavior biological adaptation to stress career career development caregiving early experience early life stress epigenetic regulation experience gene environment interaction high risk individual variation infancy infant temperament innovation interest intervention program maternal caregiving multidisciplinary neurobehavioral offspring postnatal prevent programs psychologic public health relevance resilience response stress reactivity stressor success therapy development

项目摘要

DESCRIPTION (provided by applicant): Merging the fields of epigenetics and human behavior is potentially "game changing" and provides an unprecedented opportunity to discover the molecular basis of human behavior. The goal of this mentored clinical scientist research career development award (K08) is to facilitate the candidate's development as an independent investigator specializing in epigenetic influences on infant developmental processes. [The candidate's training to date has incorporated infant physiology, early caregiving experiences, and their interaction, to investigate the development of the human stress response. But how do these early caregiving experiences become biologically embedded to explain individual variability in the response to stress? Can the study of epigenetics explain the development of normal and disordered phenotypes early in life, when the stress response is particularly malleable to early intervention?] The training and research proposed will allow the candidate to begin to answer these questions and help the candidate achieve her long-term career goal of establishing an independent research program focused on the role of epigenetic influences on normal and disordered infant and child development. Both animal (Liu et al., 1997) and human (Albers, Riksen-Walraven, Sweep, & de Weerth, 2008; Kaplan, Evans, & Monk, 2008) models demonstrate that the quality of parental caregiving affects individual susceptibility to illness throughout life, above and beyond infant temperament (Hane & Fox, 2006). Parental caregiving in infancy is typically described as a continuum ranging from caregiving sensitivity to insensitivity. Parental insensitivity is thought of as a type of early life stress that is associatd greater expressions of infant physiological reactivity. Protracted responses to stress in the form of greater physiological reactivity are in turn related to vulnerability for mental illness, diabets, obesity, and heart disease (Felitti et al., 1998; McEwen, 1998). At present, we lack clarity about how parental insensitivity translates into bio-behavioral vulnerability, though the infancy period s of particular interest given how receptive the stress system is to environmental signals (Levine, 1994). The current K08 application will examine epigenetic processes involved in the association between parenting and the infant's physiological stress response. If, as we expect, parental caregiving behavior does "calibrate" the infant stress response, this finding will impact public health in two ways, by: (1) using this basic science knowledge to support future translational work on early interventions to increase sensitive parenting which will; (2) lead to the development of targeted behavioral interventions. We know little about how the human infant stress response develops, despite evidence that: (1) both maternal caregiving behavior and epigenetic processes shape infant stress reactivity in rodents (Meaney, 2001); (2) a "reactive" infant who is reared in an adverse environment is at high risk for medical and psychological morbidity (Boyce & Ellis, 2005). The purpose of this project is to determine if similar processes occur in human infants, beyond infants' own temperamentally-based responses to stress. The aims are to: (1) evaluate the relations between maternal caregiving behavior and epigenetic alterations in candidate genes in their infants, (2) assess the relation between maternal caregiving behavior and infant physiological stress reactivity across neuroendocrine, sympathetic, and parasympathetic systems, and (3) examine the relations between maternal caregiving behavior, epigenetic alterations in candidate genes, and infant physiological stress reactivity. Translating what is known in animals to the human stress response makes this project particularly innovative. Success in this new research area is dependent upon focused mentored training and research experiences. The candidate's career development plan capitalizes on a promising opportunity to receive mentoring from a multidisciplinary team of experts who will support the candidate's career development and help her achieve her short-term goals for training in: (1) epigenetics, specifically behavioral epigenetics, (2) epigenetic laboratory methods, (3) the neuroendocrine response, particularly in relation to epigenetic changes, (4) statistical approaches to epigenetic data [and bioinformatics], and (5) professional development. This training is facilitated by a mentorship team led by Dr. Barry Lester. Dr. Lester is a developmental psychologist working at the forefront of human behavioral epigenetics, specifically in relation to infant neurobehavioral development. Dr. Lester collaborates closely with Dr. Carmen Marsit (co-mentor), a molecular biologist and epidemiologist and expert in the epigenetic regulation of the genome. Dr. Linda Carpenter (co-mentor) is a nationally recognized expert in the neuroendocrine and neurobehavioral stress response. She will provide training in the HPA system with an emphasis on epigenetics. [Dr. Uzun (consultant) will provide training in bioinformatics.] The training and research proposed will serve as the basis for a series of R01 applications spanning the basic science of behavioral epigenetics as it relates to the infant's physiological stress response.

将表观遗传学和人类行为领域合并可能会“改变游戏规则”，并为发现人类行为的分子基础提供了前所未有的机会。这个指导临床科学家研究职业发展奖（K 08）的目标是促进候选人作为独立研究者的发展，专门研究对婴儿发育过程的表观遗传影响。[The到目前为止，候选人的培训已经结合了婴儿生理学，早期的成长经历及其相互作用，以研究人类应激反应的发展。但是，这些早期的经历是如何从生物学角度解释个体对压力反应的差异的呢？当应激反应特别容易受到早期干预的影响时，表观遗传学的研究能否解释生命早期正常和紊乱表型的发展？建议的培训和研究将使候选人开始回答这些问题，并帮助候选人实现她的长期职业目标，即建立一个独立的研究计划，重点是表观遗传影响对正常和紊乱的婴儿和儿童发育的作用。两种动物（Liu等人，1997）和人类（阿尔伯斯，Riksen-Walraven，Sweep，& de Weerth，2008; Kaplan，Evans，& Monk，2008）模型表明，父母养育的质量影响个体一生中对疾病的易感性，超过婴儿气质（Hane & Fox，2006）。父母在婴儿期的养育通常被描述为从养育敏感到不敏感的连续体。父母不敏感被认为是一种早期生活压力，与婴儿生理反应的更大表达有关。以更大的生理反应性的形式对压力的主动反应反过来与精神疾病、糖尿病、肥胖症和心脏病的易感性相关（Felitti等人，1998;麦克尤恩，1998）。目前，我们还不清楚父母的不敏感如何转化为生物行为的脆弱性，尽管婴儿期特别感兴趣，因为压力系统对环境信号的接受程度很高（Levine，1994）。目前的K 08应用程序将检查参与养育和婴儿的生理应激反应之间的关联的表观遗传过程。如果正如我们所料，父母的养育行为确实“校准”了婴儿的压力反应，这一发现将通过两种方式影响公共卫生：（1）使用这一基础科学知识来支持未来早期干预的转化工作，以增加敏感的养育方式，这将导致有针对性的行为干预的发展。尽管有证据表明：（1）母亲的养育行为和表观遗传过程都会影响啮齿类动物的婴儿应激反应（Meaney，2001）;（2）在不利环境中养育的“反应性”婴儿有很高的医疗和心理发病风险（博伊斯& Ellis，2005），但我们对人类婴儿应激反应是如何发展的知之甚少。这个项目的目的是确定类似的过程是否发生在人类婴儿身上，除了婴儿自己对压力的情绪反应。其目的是：（1）评估母亲的养育行为与婴儿候选基因的表观遗传学改变之间的关系，（2）评估母亲的养育行为与婴儿神经内分泌、交感神经和副交感神经系统的生理应激反应之间的关系，以及（3）检查母亲的养育行为、候选基因的表观遗传学改变和婴儿生理应激反应之间的关系。将动物的已知知识转化为人类的应激反应，使得这个项目特别具有创新性。在这一新的研究领域的成功取决于有针对性的指导培训和研究经验。候选人的职业发展计划利用了一个很有希望的机会，接受多学科专家团队的指导，他们将支持候选人的职业发展，并帮助她实现短期培训目标：（1）表观遗传学，特别是行为表观遗传学，（2）表观遗传学实验室方法，（3）神经内分泌反应，特别是与表观遗传变化有关的反应，（4）表观遗传数据[和生物信息学]的统计方法，（5）专业发展。该培训由巴里莱斯特博士领导的导师团队提供便利。莱斯特博士是一位发展心理学家，致力于人类行为表观遗传学的研究，特别是与婴儿神经行为发育有关的研究。Lester博士与Carmen Marsit博士（共同导师）密切合作，Carmen Marsit博士是分子生物学家和流行病学家，也是基因组表观遗传调控方面的专家。琳达卡彭特博士（共同导师）是神经内分泌和神经行为应激反应方面的国家公认的专家。她将提供HPA系统的培训，重点是表观遗传学。[Dr. Uzun（顾问）将提供生物信息学培训。拟议的培训和研究将作为一系列R 01应用的基础，涵盖了行为表观遗传学的基础科学，因为它涉及到婴儿的生理应激反应。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prenatal Stress, Fearfulness, and the Epigenome: Exploratory Analysis of Sex Differences in DNA Methylation of the Glucocorticoid Receptor Gene.

产前压力、恐惧和表观基因组：糖皮质激素受体基因 DNA 甲基化性别差异的探索性分析。

DOI：
10.3389/fnbeh.2016.00147
发表时间：
2016
期刊：
Frontiers in behavioral neuroscience
影响因子：
3
作者：
Ostlund,BrendanD;Conradt,Elisabeth;Crowell,SheilaE;Tyrka,AudreyR;Marsit,CarmenJ;Lester,BarryM
通讯作者：
Lester,BarryM

Incorporating epigenetic mechanisms to advance fetal programming theories.