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

描述(申请人提供)：将表观遗传学和人类行为领域结合起来，可能会改变游戏规则，为发现人类行为的分子基础提供了前所未有的机会。这个有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作为一名独立研究员的发展，专门研究表观遗传对婴儿发育过程的影响。[到目前为止，候选人的培训结合了婴儿生理学、早期护理经验以及它们之间的相互作用，以调查人类应激反应的发展。但是，这些早期的照料经历如何在生物学上根植于解释个体在应对压力时的差异性？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，而此时的应激反应特别容易受到早期干预的影响？拟议的培训和研究将允许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，专注于表观遗传影响对正常和紊乱婴儿和儿童发育的作用。动物模型(Liu et al.，1997)和人类模型(Albers，Riksen-Walraven，Sweep，&de Weerth，2008；Kaplan，Evans，&Monk，2008)都表明，父母照料的质量影响个体一生中对疾病的易感性，超过婴儿的气质(Hane&Fox，2006)。父母在婴儿期的照顾通常被描述为一个从照顾敏感到麻木不仁的连续体。父母的麻木不仁被认为是一种早期生活压力，与婴儿的生理反应能力更强有关。以更强的生理反应形式对压力的长期反应反过来又与精神疾病、糖尿病、肥胖症和心脏病的脆弱性有关(Felitti等人，1998；McEwen，1998)。目前，我们还不清楚父母的麻木不仁如何转化为生物行为的脆弱性，尽管婴儿期的S特别感兴趣，因为压力系统对环境信号的接受程度(Levine，1994)。目前的K08应用程序将研究父母养育和婴儿生理应激反应之间的关联所涉及的表观遗传过程。如果正如我们预期的那样，父母的照料行为确实“校准”了婴儿的压力反应，这一发现将以两种方式影响公共健康：(1)使用这一基础科学知识来支持未来关于早期干预的转化工作，以增加敏感的父母养育；(2)导致有针对性的行为干预的发展。我们对婴儿的压力反应如何发展知之甚少，尽管有证据表明：(1)母亲的照料行为和表观遗传过程都塑造了啮齿动物的婴儿应激反应(Meaney，2001)；(2)在不利环境中长大的“反应性”婴儿有很高的医疗和心理疾病风险(Boyce&Ellis，2005)。这个项目的目的是确定除了婴儿自身对压力的气质反应外，人类婴儿是否也有类似的过程。本研究的目的是：(1)评估母亲照料行为与婴儿候选基因的表观遗传改变之间的关系；(2)评估母亲照料行为与婴儿神经内分泌、交感和副交感神经系统的生理应激反应之间的关系；(3)检验母亲照料行为、候选基因的表观遗传改变与婴儿生理应激反应之间的关系。将动物身上已知的东西转化为人类的压力反应，这使得这个项目特别具有创新性。这一新研究领域的成功有赖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一个很有希望的机会接受多学科专家团队的指导，这些专家将支持候选人的职业发展并帮助她实现短期培训目标，培训内容包括：(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，特别是与表观遗传学变化有关的神经内分泌反应，(4)表观遗传学数据的统计方法[和生物信息学]， (5)职业发展。这项培训是由巴里·莱斯特博士领导的指导团队推动的。莱斯特博士是一名发展心理学家，致力于人类行为表观遗传学的前沿研究，特别是与婴儿神经行为发育有关的研究。莱斯特博士与卡门·马西特博士(共同导师)密切合作，卡门·马西特博士是一名分子生物学家、流行病学家和基因组表观遗传调控专家。琳达·卡彭特博士(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系统的培训，重点是表观遗传学。[乌昆博士(顾问)将提供生物信息学方面的培训。]拟议的培训和研究将 作为跨越行为表观遗传学基础科学的一系列R01应用的基础，因为它与婴儿的生理应激反应有关。

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.