Maladaptive Stress Response in Children: A Feasibility Study

描述（由申请人提供）：童年逆境与抑郁症，创伤后精神障碍（PTSD）和疾病脆弱性的风险增加有关，这种风险持续到成年。这种早期逆境的长期影响归因于“重新编程”或 调节下丘脑-垂体-肾上腺（HPA）轴和免疫反应的基因表达的变化，影响生物和心理过程。HPA轴的激活是对压力的适应性反应;然而，当在数周或数月内反复激活时，可能导致HPA轴失调。这种失调与抑郁症和创伤后应激障碍有关，尽管描述了不一致的神经内分泌特征。在抑郁症中，皮质醇水平升高，糖皮质激素受体（GR）反应性降低，而在创伤后应激障碍中，皮质醇水平降低，GR反应性增强。某些神经内分泌特征可能反映了一种预先存在的脆弱性，这种脆弱性使个体在应对压力时面临不同的结果。直到最近，评估HPA轴之前的压力是不可能的。头发皮质醇分析，一种最先进的方法，提供了一个长期的HPA轴活动的回顾性措施。我们的目标是招募40名15-18岁的儿童，他们的父母在父母诊断后两周内被诊断为IV期肺癌，并将他们与20名父母/兄弟姐妹没有癌症或任何慢性疾病的对照儿童进行比较。两组将在摄入后6个月和9个月进行随访。在摄入和6个月时，我们建议收集血液样本，以量化HPA轴和GR敏感性的基因表达。我们测量头发皮质醇浓度（HCC）在最接近头皮的头发的2厘米段，这反映了HPA轴的活动在过去的两个月，因此在父母诊断为第一次评估。我们还收集唾液皮质醇的短期HPA轴活动。我们在入院和随访时测量临床结果。我们假设父母患有癌症的儿童在2周时对父母诊断的急性应激反应会表现出GR表达和总唾液皮质醇分泌的增加。在6个月时，作为对父母诊断的慢性压力的反应，父母患有癌症的儿童中GR表达降低，炎症基因表达增加。这些将与GR敏感性降低和HCC和唾液皮质醇增加有关。压力前的HCC将与先前的创伤呈负相关，并将预测对急性和慢性压力的生物反应，这反过来又将预测抑郁症和PTSD病理学以及其他健康结果。这项R21试点研究将收集研究设计的可行性数据，并将告知我们提出的生物模型的各个途径，该模型将儿童时期的慢性压力与精神疾病和疾病脆弱性风险增加联系起来，通过改变 基因表达和生理反应的生物过程。这个R21为未来的项目奠定了基础，该项目将确定早期生物标志物，这些生物标志物标志着适应不良应激反应的风险，并为新的预防和治疗方法提供目标。

DESCRIPTION (provided by applicant): Childhood adversity is associated with increased risk for depression, posttraumatic disorder (PTSD), and disease vulnerability, a risk that continues into adulthood. This long-lasting impact of early adversity is attributed to the "reprogramming" or changes in the expression of genes regulating the hypothalamic-pituitary- adrenal (HPA) axis and immune responses, which impact biological and psychological processes. Activation of the HPA axis is an adaptive response to stress; however, when repeatedly activated over weeks or months, HPA axis dysregulation can result. Such dysregulation is associated with both depression and PTSD although a discrepant neuroendocrine profile is described. In depression, there are increased cortisol and reduced glucocorticoid receptor (GR) responsiveness whereas in PTSD, there are attenuated cortisol levels and enhanced GR responsiveness. It is possible that certain neuroendocrine profiles reflect a pre-existing vulnerability that puts individuals at isk for different outcomes in response to stress. Until recently, the assessment of HPA axis prior to stress would not have been possible. Hair cortisol analysis, a state of the art method, provides a retrospective measure of long-term HPA axis activity. Our aims are to recruit 40 children, 15-18 years of age, of parents diagnosed with stage IV lung cancer within two weeks of parental diagnosis and compare them to 20 control children whose parents/siblings do not have cancer or any chronic illnesses. The two groups will be followed 6 and 9 months after intake. At intake and 6 months, we propose to collect blood samples to quantify gene expression in the HPA axis and GR sensitivity. We measure hair cortisol concentrations (HCC) in the 2 cm segment of hair closest to the scalp, which reflects HPA axis activity over the past two months, and thus prior to parental diagnosis for the first assessment. We also collect salivary cortisol for short-term HPA axis activity. We measure clinical outcomes at intake and follow-ups. We hypothesize that children of parents with cancer will show increased GR expression and total salivary cortisol output in response to the acute stress of parental diagnosis at 2 weeks. At 6 months and in response to the chronic stress of parental diagnosis, there will be decreased GR expression and increased expression of inflammatory genes in children of parents with cancer. These will be associated with reduced GR sensitivity and increased HCC and salivary cortisol. HCC prior to stress will be negatively associated with prior trauma and will predict biological responses to acute and chronic stress, which will in turn predict depression and PTSD symptomatology, and other health outcomes. This R21 pilot study will gather feasibility data of the study design and will inform individual pathways of our proposed biological model that links chronic stress in childhood to increased risk of psychiatric illness and disease vulnerability through alterations in biological processes of gene expression and physiological responses. This R21 lays the foundation for a future project that will identify early biomarkers that signal risk for maladaptiv stress response and provide targets for new prevention and treatment approaches.