Maladaptive Stress Response in Children: A Feasibility Study

儿童适应不良压力反应：可行性研究

• 批准号: 8875776
• 负责人: Nadine M. Melhem
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875776
• 关键词: 18 year old; Adult; Attenuated; Behavioral; Biological; Biological Markers; Biological Models; Biological Process; Blood specimen; Cancer Patient; Caregivers; Child; Childhood; Chronic Disease; Chronic stress; Clinical; Comorbidity; Control Groups; Data; Diagnosis; Diagnostic Neoplasm Staging; Disasters; Disease; Evaluation; Feasibility Studies; Foundations; Future; Gene Expression; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Hair; Health; Hydrocortisone; Immune; Immune response; Individual; Inflammation; Inflammatory; Intake; Interleukin-1; Interleukin-2; Interleukin-6; Interleukin-8; Life; Link; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mental Depression; Mental disorders; Methods; Negative Valence; Neurobiology; Neurosecretory Systems; Newly Diagnosed; Nuclear; Outcome; Output; Parents; Pathway interactions; Patient Self-Report; Pattern; Physiological; Pilot Projects; Population; Post-Traumatic Stress Disorders; Prevention; Preventive Intervention; Process; Processed Genes; Recording of previous events; Recruitment Activity; Research; Research Design; Risk; Salivary; Sampling; Scalp structure; Siblings; Signal Pathway; Signal Transduction; Staging; Stress; TNF gene; Target Populations; Tissue-Specific Gene Expression; Trauma; Tumor Necrosis Factor-alpha; abuse neglect; acute stress; aged; biological adaptation to stress; biological systems; cancer diagnosis; drug discovery; high risk; human subject; hypothalamic-pituitary-adrenal axis; man; psychologic; receptor expression; receptor sensitivity; response; stressor

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.

描述（由申请人提供）：儿童逆境与抑郁症，创伤后疾病（PTSD）和疾病脆弱性的风险增加有关，这种风险一直持续到成年。早期逆境的这种长期影响归因于“重编程”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，这会影响生物学和心理过程。 HPA轴的激活是对应力的适应性反应。但是，当在数周或几个月中反复激活时，HPA轴失调可能会导致。尽管描述了差异神经内分泌谱，但这种失调与抑郁症和PTSD都相关。在抑郁症中，皮质醇和糖皮质激素受体（GR）的反应性降低，而在PTSD中，皮质醇水平减弱并增强了GR反应性。某些神经内分泌特征可能反映了一个现有的脆弱性，该脆弱性使个人在响应压力方面的不同结果使个人处于ISK。直到最近，还不能在应力之前对HPA轴进行评估。头发皮质醇分析是一种最先进的方法，它提供了长期HPA轴活动的回顾性度量。我们的目标是在父母诊断后的两周内招募40名15-18岁的父母，被诊断出患有IV期肺癌的父母，并将他们与20名对照儿童进行比较，他们的父母/兄弟姐妹没有癌症或任何慢性病。两组将在摄入后6和9个月进行。在摄入量和6个月时，我们建议收集血样，以量化HPA轴和GR灵敏度中的基因表达。我们在最接近头皮的2 cm头发段中测量头发皮质醇浓度（HCC），这反映了过去两个月中HPA轴的活性，因此在父母诊断之前进行了首次评估。我们还收集用于短期HPA轴活动的唾液皮质醇。我们测量摄入量和随访时的临床结果。我们假设癌症父母的孩子将显示GR表达增加和总唾液皮质醇输出，这是对父母诊断2周的急性应力的响应。在6个月时，为了响应父母诊断的慢性应激，GR表达和炎症基因表达的降低和癌症儿童的表达增加。这些将与降低的GR敏感性以及HCC和唾液皮质醇的增加有关。在压力之前的HCC将与先前的创伤负相关，并将预测对急性和慢性压力的生物学反应，这反过来又可以预测抑郁症和PTSD症状，以及其他健康状况。这项R21试点研究将收集研究设计的可行性数据，并将为我们提出的生物学模型的各个途径提供信息，该模型将儿童期间的慢性压力与增加精神病的风险和疾病脆弱性联系在一起。 基因表达和生理反应的生物学过程。该R21为未来的项目奠定了基础，该项目将确定早期的生物标志物，这表明疾病疾病的压力反应风险并为新的预防和治疗方法提供目标。