Perinatal Programming of Infant Stress Reactivity and the Atopic Phenotype

描述（由申请人提供）：对环境刺激的生物超敏反应是特应性的基本特征，使个体易患一系列疾病，如过敏性鼻炎、特应性皮炎和过敏性哮喘。随着我们对特应性疾病的自然史和病理生理学以及应激的神经生物学的理解，将心理应激与特应性表达联系起来的证据越来越多。然而，所涉及的具体途径仍有待于在人体研究中阐明。研究结果表明，压力可能会影响发病机制，引起失调的生物行为状态（例如，抑郁症，创伤后应激障碍），这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压力源，发育期间的慢性压力源，创伤事件）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调节紊乱（例如，下丘脑-垂体-肾上腺轴，交感神经-肾上腺-髓质系统）可以从子宫内开始调节后代的免疫功能。因此，了解母亲在怀孕期间这些系统的失调可能特别有益。非最佳的早期体验（例如，母亲的精神病理学、母亲的不敏感性）也可能通过导致婴儿情绪调节和神经免疫发育中断来影响这些过程，从而为对刺激的反应性改变和炎症过程（早期特应性的标志）奠定基础。探索这些联系可能与城市人群特别相关，他们不成比例地承受着压力和慢性特应性疾病的负担。我们将研究产妇压力（围产期压力，终身创伤）的影响，在城市样本（N=275）的儿童特应性的表达。我们将纳入战略研究压力反应在怀孕期间，婴儿期和幼儿期，以阐明途径从压力到一个层次的早期中间表型，可能与持续性特应性疾病（早期致敏指数IgE表达和皮肤试验反应性，T辅助细胞分化，气道阻力，早期临床表型）。我们将研究干预过程如何影响这些关系，包括母胎压力的内分泌指标（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养育行为影响婴儿应激反应（皮质醇，呼吸，交感神经和副交感神经自主功能），在6个月大时的标准化实验室方案中评估，和30个月内评估的儿童特应性特征。在这个前瞻性设计中，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或受产后因素的影响。我们将测试近端和终身应力暴露对拟议途径的贡献。研究结果可以确定导致和维持昂贵的儿童特应性疾病的早期易感性的机制，为更有效的预防和干预策略提供信息。

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.