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

描述（由申请人提供）：表观遗传学和人类行为领域的合并可能会“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。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一名独立的研究者，专门研究表观遗传对婴儿发育过程的影响。[候选人的培训迄今已纳入婴儿生理学，早期护理经验，以及他们之间的相互作用，以调查人类压力反应的发展。]但是，这些早期的照顾经历是如何在生物学上解释个体对压力反应的差异性的呢？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，当时的应激反应特别容易受到早期干预的影响？建议的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，即建立一个独立的研究项目，重点研究表观遗传对正常和紊乱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）都表明，父母照顾的质量会影响个体一生中对疾病的易感性，而不仅仅是婴儿气质（Hane & Fox, 2006）。父母在婴儿期的照顾通常被描述为一个连续体，从照顾敏感到不敏感。父母的不敏感被认为是一种早期生活压力，它与婴儿生理反应的更大表达有关。以更强的生理反应形式表现出来的对压力的长期反应反过来又与精神疾病、糖尿病、肥胖症和心脏病的易感性相关（Felitti et al., 1998; McEwen, 1998）。目前，我们还不清楚父母的不敏感是如何转化为生物行为脆弱性的，尽管考虑到压力系统对环境信号的接受程度，婴儿期是特别有趣的（Levine, 1994）。目前的K08应用程序将检查表观遗传过程涉及的关系之间的父母和婴儿的生理应激反应。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，那么这一发现将从两个方面影响公共卫生，：(1)利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，以提高父母的敏感性。(2)导致有针对性的行为干预的发展。我们对人类婴儿应激反应是如何发展的知之甚少，尽管有证据表明：(1)母亲的照顾行为和表观遗传过程都影响了啮齿动物婴儿的应激反应（Meaney, 2001）；(2)在不利环境中长大的“反应性”婴儿在医疗和心理疾病方面的风险很高（Boyce & Ellis, 2005）。这个项目的目的是确定类似的过程是否也发生在人类婴儿身上，而不仅仅是婴儿自身对压力的基于气质的反应。本研究的目的是：(1)评估母亲照顾行为与婴儿候选基因表观遗传改变之间的关系；(2)评估母亲照顾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)研究母亲照顾行为、候选基因表观遗传改变与婴儿生理应激反应之间的关系。将已知的动物应激反应转化为人类应激反应使这个项目特别具有创新性。在这个新的研究领域的成功取决于重点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前途的机会，接受一个多学科专家团队的指导，该团队将支持候选人的职业发展，并帮助她实现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，(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，(4)表观遗传数据的统计方法[和生物信息学]，

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.