Perinatal Programming of Infant Stress Reactivity and the Atopic Phenotype

描述(由申请人提供)：对环境刺激的生物过敏是特应性疾病的一个基本特征，使个体容易患上一系列疾病、过敏性鼻炎、特应性皮炎和过敏性哮喘。随着我们对特应性疾病的自然历史和病理生理学以及应激的神经生物学的了解的加深，将心理应激与特应性表达联系起来的证据越来越多。然而，涉及的具体途径仍有待在人体研究中阐明。研究结果表明，应激源可能通过引起失调的生物行为状态(如抑郁、创伤后应激障碍)来影响发病机制，这些状态对影响疾病风险的生理过程产生影响。极端形式的压力暴露(同一时间段内的多种应激源、发育期的慢性应激源、创伤性事件)更有可能导致持续的心理和生理变化。内分泌和自主神经系统(如下丘脑-垂体-肾上腺轴、交感-肾上腺-髓质系统)的调节紊乱可能会从子宫开始调节后代的免疫功能。因此，了解怀孕期间母亲对这些系统的失调可能特别有意义。非最佳的早期照料经历(例如，母亲精神病理学、母亲不敏感)也可能影响这些过程，导致婴儿情绪调节和神经免疫发育中断，为对刺激和炎症过程的反应改变铺平道路，这些都是早期特应性反应的特征。探索这些联系在城市人群中可能特别相关，他们承受着不成比例的压力和慢性特应性疾病的负担。我们将在一个城市样本(N=275)中检验母亲应激(累积围产期应激，终生创伤)对儿童特应症表达的影响。我们将结合研究孕期、婴儿期和儿童早期应激反应的策略，阐明从应激到可能与持续性特应性疾病(以IgE表达和皮试反应、T辅助细胞分化、呼吸道阻力、早期临床表型为指标的早期致敏)相关的早期中间表型分级的途径。我们将研究干预过程如何影响这些关系，包括母胎内分泌应激指标(产前皮质醇、促肾上腺皮质激素释放激素)、产前/产后母体心理功能和产后照料行为如何影响婴儿的应激反应(皮质醇、呼吸、交感和副交感自主神经功能)，在6个月大的标准化实验室方案中进行评估，以及在30个月内评估儿童特应性特征。在这项前瞻性设计中，我们将研究胎儿应激暴露如何影响早期神经免疫发育，以及这种影响如何独立于出生后因素或受到出生后因素的调节。我们将测试近端和终生应激暴露对所提出的通路的贡献。研究结果可能确定导致和维持代价高昂的儿科特应性疾病早期易感性的机制，为更有效的预防和干预策略提供信息。 公共卫生相关性：这项研究可能会增加我们对围产期母体应激对早期中间表型易感性的影响的理解，这些表型可能倾向于在儿童时期发展为特应性疾病的后续风险。这些知识可能有助于设计预防特应性疾病发展的计划，如哮喘、过敏性鼻炎和湿疹，特别是在城市高危人群中。鉴于美国特应性患者的管理成本巨大，了解特应性患者发展的早期阶段将为社会带来巨大的潜在好处。

DESCRIPTION (provided by applicant): Biological hypersensitivity to environmental stimuli is a fundamental feature of atopy, predisposing individuals to a spectrum of disorders, allergic rhinitis, atopic dermatitis, and allergic asthma. Evidence linking psychological stress to atopy expression has grown with our increased understanding of the natural history and pathophysiology of atopic disorders and the neurobiology of stress. However, the specific pathways involved remain to be elucidated in human studies. Findings suggest that stressors may influence pathogenesis by causing dysregulated biobehavioral states (e.g., depression, PTSD), which exert effects on physiological processes that influence disease risk. Extreme forms of stress exposure (multiple stressors within the same time period, chronic stressors over developmental periods, traumatic events) are more likely to lead to persistent psychological and physiological alterations. Disturbed regulation of endocrine and autonomic systems (e.g., hypothalamic-pituitary-adrenal axis, sympathetic-adrenal-medullary system) may modulate offspring immune functioning beginning in utero. Therefore, understanding maternal dysregulation of these systems in pregnancy may be particularly informative. Non-optimal early caregiving experiences (e.g., maternal psychopathology, maternal insensitivity) may also impact these processes by leading to disrupted infant emotion regulation and neuroimmune development, setting the stage for altered reactivity to stimuli and inflammatory processes, hallmarks of early atopy. Exploring these links may be particularly relevant in urban populations, who are disproportionately burdened by both stress and chronic atopic disorders. We will examine the effects of maternal stress (cumulative perinatal stress, lifetime trauma), on the expression of child atopy in an urban sample (N=275). We will incorporate strategies for studying stress reactivity during pregnancy, infancy, and early childhood to elucidate pathways from stress to a hierarchy of early intermediate phenotypes that may be related to persistent atopic disorders (early sensitization as indexed by IgE expression and skin test reactivity, T-helper cell differentiation, airway resistance, early clinical phenotypes). We will examine how intervening processes may affect these relationships, including how maternal-fetal endocrine indicators of stress (prenatal cortisol, corticotrophin-releasing hormone), pre/postnatal maternal psychological functioning, and postnatal caregiving behaviors impact the infant stress response (cortisol, respiration, sympathetic and parasympathetic autonomic functioning), assessed during a standardized laboratory protocol at age 6 months, and child atopic profiles assessed through 30 months. In this prospective design, we will examine how fetal stress exposure may influence early neuroimmune development and how such effects are independent of or moderated by postnatal factors. We will test the contributions of proximal and lifetime stress exposures on the proposed pathways. The study findings may identify mechanisms that lead to and maintain early predisposition to costly pediatric atopic disorders, informing more efficacious prevention and intervention strategies. PUBLIC HEALTH RELEVANCE: This study may increase our understanding of the effects of perinatal maternal stress on vulnerability to early intermediate phenotypes that may predispose to subsequent risk for developing atopic disorders in childhood. Such knowledge may inform efforts to design programs to prevent the development of atopic disorders, such as asthma, allergic rhinitis and eczema, particularly in high-risk urban populations. Given the enormous cost in the management of atopic patients in the United States, understanding the earliest stages of development offers significant potential benefits to society.