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：
8911396
负责人：
Liz D Conradt
金额：
$ 12.39万
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/8911396
关键词：
Affect Animals Area Basic Behavioral Science Basic Science Behavior Behavior Therapy Behavioral Bioinformatics Biological Candidate Disease Gene Child Development Clinical DNA Methylation Data Development Development Plans Developmental Process Diabetes Mellitus Disease Disease susceptibility Early Intervention Environment Epidemiologist Epigenetic Process Exhibits Foxes Future Gene Expression Genes Genome Glucocorticoid Receptor Goals Health Heart Diseases Hippocampus (Brain)Human Human Development Individual Infant Infant Behavior Intervention Studies K-Series Research Career Programs Knowledge Laboratories Lead Life Life Experience Life Stress Link Literature Mediating Medical Mental disorders Mentors Mentorship Methods Methylation Modeling Molecular Morbidity - disease rate NR3C1 gene Neurosecretory Systems Obesity Parenting behavior Pharmaceutical Preparations Phenotype Physiological Physiology Population Predisposition Problem behavior Process Psychologist Public Health Receptor Gene Regulation Research Research Personnel Research Training Rodent Rodent Model Role Scientist Series Shapes Signal Transduction Stress System Time Tissues Training Translating Variant Work base biological adaptation to stress career career development caregiving early experience experience gene environment interaction high risk infancy infant temperament innovation interest intervention program multidisciplinary neurobehavioral offspring postnatal prevent programs psychologic resilience response stressor success

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.

描述（由申请人提供）：合并表观遗传学和人类行为的领域可能是“改变游戏的”，并提供了一个前所未有的机会来发现人类行为的分子基础。这项指导的临床科学家研究职业发展奖（K08）的目标是促进候选人的发展，成为专门研究对婴儿发育过程的独立研究人员的发展。 [迄今为止，候选人的培训纳入了婴儿的生理学，早期的护理经验及其相互作用，以调查人类压力反应的发展。但是，这些早期的护理经历如何在生物学上嵌入以解释压力反应中的个体变异性？对表观遗传学的研究能否解释生活早期正常和无序表型的发展，当压力反应特别适合早期干预时？]培训和研究将使候选人能够开始回答这些问题并帮助候选人实现她的长期职业目标，即建立了针对正常和疾病的独立研究计划的独立研究计划，以实现正常和儿童发育的作用。动物（Liu等，1997）和人类（Albers，Riksen-Walraven，Sweep，＆De Weerth，2008; Kaplan，Evans和Monk，＆Monk，2008）模型都表明，父母照顾的质量会影响整个生命的个体易感性，超越婴儿气候（Hane＆Fox，Hane＆Fox，2006年）。婴儿期的父母照顾通常被描述为从照料敏感性到不敏感的连续体。父母不敏感被认为是一种早期的生命压力，它是婴儿生理反应性的更大表达。以更大的生理反应性形式对压力的持久反应反过来又与精神疾病，糖尿病，肥胖和心脏病的脆弱性有关（Felitti等，1998； McEwen，1998）。目前，我们缺乏对父母不敏感性如何转化为生物行为脆弱性的清楚，尽管考虑到压力系统对环境信号的接受程度特别感兴趣的婴儿期。当前的K08应用将检查育儿与婴儿生理压力反应之间关联的表观遗传过程。如果正如我们期望的那样，父母的照顾行为确实“校准”了婴儿的压力反应，这一发现将通过以下方式以两种方式影响公共卫生，（1）使用这种基本科学知识来支持未来的关于早期干预措施的翻译工作，以增加敏感的育儿，这将；（2）导致靶向行为干预的发展。尽管有证据表明：（1）孕产妇的护理行为和表观遗传学过程塑造了啮齿动物的婴儿胁迫反应性，但我们对人类婴儿压力反应的发展知之甚少（Meaney，2001）；（2）在不利环境中饲养的“反应性”婴儿患医学和心理发病率的风险很高（Boyce＆Ellis，2005）。该项目的目的是确定人类婴儿中是否发生了类似的过程，除了婴儿对压力的气质反应之外。目的是：（1）评估孕妇护理行为与婴儿中候选基因的表观遗传变化之间的关系，（2）评估孕产妇护理行为与婴儿的生理压力反应之间的关系，跨神经内分泌，交感神经，副交感神经系统和副心理系统，以及（3）孕产妇护理疗法的关系，替代性均反应性稳定性阶段阶段性质量阶段，质量固有性。将动物中已知的内容转换为人类压力反应，使该项目特别创新。在这个新研究领域的成功取决于重点的指导培训和研究经验。候选人的职业发展计划利用了有前途的机会，从多学科的专家团队那里获得指导，这些专家将支持候选人的职业发展，并帮助她实现她在以下方面的短期培训目标：（1）表观遗传学，特别是行为表观遗传学，特别是表观遗传学实验室方法，（2）表观遗传学方法，尤其是对神经元素的方法，尤其是Epecentity（Epceentic）（Epceentic）（4） [和生物信息学]，（5）专业发展。这项培训由Barry Lester博士领导的指导团队促进了这项培训。莱斯特博士是一名发展心理学家，在人类行为表观遗传学的最前沿，特别是与婴儿神经行为发展有关的发展。莱斯特博士与分子生物学家兼流行病学家兼基因组表观遗传调节专家Carmen Marsit博士（Co-Contor）紧密合作。琳达·卡彭特（Linda Carpenter）博士（Co-Incertor）是神经内分泌和神经性压力反应的全国认可的专家。她将在HPA系统中提供培训，重点是表观遗传学。 [博士Uzun（顾问）将提供生物信息学的培训。]提议的培训和研究将作为与婴儿的生理压力反应有关的行为表观遗传学基础科学的一系列R01应用的基础。