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

• 批准号: 9326276
• 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
• 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/9326276
• 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; Early Intervention; Environment; Epidemiologist; Epigenetic Process; Exhibits; Foxes; Future; Gene Expression; Genes; Genome; Glucocorticoid Receptor; Goals; Health; Heart Diseases; Hippocampus (Brain); Human; Individual; Infant; 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; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Predisposition; Problem behavior; Process; Program Development; 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; epigenetic regulation; experience; gene environment interaction; high risk; infancy; infant temperament; innovation; interest; maternal caregiving; multidisciplinary; neurobehavioral; offspring; postnatal; prevent; programs; psychologic; public health relevance; research and development; resilience; response; stress reactivity; stressor; success; therapy development

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）：表观遗传学和人类行为领域的融合可能会“改变游戏规则”，并为发现人类行为的分子基础提供前所未有的机会。该指导临床科学家研究职业发展奖（K08）的目标是促进候选人发展成为专门研究表观遗传对婴儿发育过程影响的独立研究者。 [候选人迄今为止的培训已纳入婴儿生理学、早期护理经验及其相互作用，以研究人类压力反应的发展。但是，这些早期的护理经历是如何在生物学上嵌入的，以解释个体对压力反应的变异性呢？表观遗传学研究能否解释生命早期正常和紊乱表型的发展，此时压力反应特别容易受到早期干预的影响？] 拟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目标长期职业目标是建立一个独立的研究项目，重点关注表观遗传对正常和紊乱的婴儿和儿童发育的影响。动物模型（Liu et al., 1997）和人类模型（Albers, Riksen-Walraven, Sweep, & de Weerth, 2008；Kaplan, Evans, & Monk, 2008）模型都表明，父母照顾的质量会影响个体对疾病的易感性。生活，超越婴儿气质（Hane＆Fox，2006）。婴儿期父母的照顾通常被描述为从照顾敏感到不敏感的连续体。父母的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现有关。以更大的生理反应形式出现的对压力的长期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 et al., 1998; McEwen, 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，尽管考虑到压力系统对环境信号的接受程度，婴儿期特别令人感兴趣（Levine，1994）。当前的 K08 应用程序将检查涉及养育和婴儿生理应激反应之间关联的表观遗传过程。如果正如我们所期望的那样，父母的照顾行为确实“校准”了婴儿的压力反应，那么这一发现将以两种方式影响公共健康：（1）利用这些基础科学知识来支持未来早期干预的转化工作，以增强敏感的养育方式哪个会； (2) 导致有针对性的行为干预措施的发展。我们对人类婴儿应激反应如何发展知之甚少，尽管有证据表明：（1）母亲的照顾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) 在不利环境中长大的“反应性”婴儿出现医学和心理疾病的风险很高(Boyce & Ellis, 2005)。该项目的目的是确定除了婴儿自身对压力的气质反应之外，类似的过程是否也发生在人类婴儿身上。目的是：（1）评估母亲的照顾行为与婴儿候选基因表观遗传改变之间的关系，（2）评估母亲的照顾行为与婴儿跨神经内分泌、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)检查母亲的照顾行为、候选基因的表观遗传改变和婴儿生理应激反应之间的关系。将动物中已知的知识转化为人类的压力反应使该项目特别具有创新性。这一新研究领域的成功取决于重点指导的培训和研究经验。候选人的职业发展计划利用了一个有前途的机会，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 ）表观遗传实验室方法，（3）神经内分泌反应，特别是与表观遗传变化相关的反应，（4）表观遗传数据的统计方法[和生物信息学]， (5) 专业发展。该培训由 Barry Lester 博士领导的导师团队负责推动。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前沿，特别是与婴儿神经行为发育相关的研究。 Lester 博士与分子生物学家、流行病学家、基因组表观遗传调控专家 Carmen Marsit 博士（共同导师）密切合作。 Linda Carpenter 博士（共同导师）是全国公认的神经内分泌和神经行为应激反应专家。她将提供 HPA 系统方面的培训，重点是表观遗传学。 [博士。 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 R01 应用的基础，涵盖行为表观遗传学基础科学，因为它与婴儿的生理应激反应有关。