Biomarkers in the HPA axis and inflammatory pathways for maladaptive stress response in children

HPA 轴的生物标志物和儿童适应不良应激反应的炎症通路

• 批准号: 9475313
• 负责人: Nadine M. Melhem
• 金额: $ 65.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-21 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9475313
• 关键词: Adult; Age; Attenuated; Behavioral; Biological; Biological Markers; C-reactive protein; Cessation of life; Child; Childhood; Chronic; Chronic Disease; Chronic stress; Clinical Data; Comorbidity; Development; Diagnosis; Disease; Family; Feasibility Studies; Feeling suicidal; Gene Expression; Genes; Glucocorticoid Receptor; Goals; Hair; Hydrocortisone; Hyperactive behavior; Immune response; Incidence; Inflammation; Inflammatory; Intake; Interleukin-1 beta; Longitudinal Studies; Malignant Neoplasms; Measures; Mental Depression; Mental disorders; Neurobiology; Neurosecretory Systems; Newly Diagnosed; Parent-Child Relations; Parents; Pathway interactions; Pattern; Population; Post-Traumatic Stress Disorders; Preventive Intervention; Psychopathology; Puberty; Quality of life; Recording of previous events; Research Infrastructure; Risk; Salivary; Siblings; Signal Transduction; Stress; Suicide; TNF gene; Target Populations; Time; aged; biological adaptation to stress; biological systems; cancer diagnosis; cytokine; high risk; hypothalamic-pituitary-adrenal axis; inflammatory marker; novel; protective factors; receptor sensitivity; recruit; response; response biomarker; sex; stressor; suicidal patient; suicidal risk; symptomatology

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is an adaptive response to stress. However, when repeatedly activated, HPA axis dysregulation can result. Stress in childhood alters biological systems and the expression of genes regulating HPA axis and immune responses in a manner that persists across decades. Stress is also associated with increased risk for depression and PTSD, a risk that continues into adulthood, and both are associated with increased risk for suicidality. However different neuroendocrine profiles are described with increased cortisol and reduced glucocorticoid receptor (GR) responsiveness in depression; and attenuated cortisol and enhanced GR responsiveness in PTSD. Inflammation, also associated with stress, is believed to result from reduced GR sensitivity, possibly as a result of chronically elevated cortisol. Yet inflammation is associated with both depression and PTSD, which is difficult to rectify with their apparently differential pattern of GR responsiveness. The discrepant HPA axis profiles also do not conform with the high comorbidity rate between these disorders. Our overarching goal is to examine the trajectories of the HPA axis and inflammatory pathways in response to stress in children; and identify biological trajectories that predict maladaptive stress responses. We propose to recruit 200 children, aged 12-17 years, of parents newly diagnosed with advanced stage cancer (stress) within 3 months of diagnosis (intake) and follow them at 6 and 18 months following intake. This population will allow us to study the unfolding of stress responses, which is almost impossible to capture for other stressors. We will also recruit and follow 100 children from families where a parent or siblings do not have cancer or chronic illness or death (controls). We propose to measure gene expression in the HPA axis and inflammatory pathways; hair cortisol concentrations (HCC) to measure chronic HPA axis activity; salivary cortisol to measure cortisol awakening response (CAR); GR sensitivity; C- Reactive Protein and inflammatory cytokines; and collect clinical data. We hypothesize that within 3 months of parental diagnosis, stress children will show increased expression of HPA axis and inflammatory genes and increased HCC, CAR, and inflammatory markers compared to controls; but no differences in GR sensitivity. In response to chronic stress, stress children will show decreased expression of HPA axis genes, enhanced GR sensitivity, and decreased HCC and CAR over time compared to controls. They will also continue to show increased expression of inflammatory genes and inflammation. Biological responses early on and their trajectories will predict symptomatology (depression, PTSD, and suicidal ideation) and onset of depression and PTSD; and these relationships will be influenced by pre-existing and ongoing vulnerability and protective factors. This study will advance our understanding of the neurobiological, environmental, and behavioral pathways of stress responses in children and its impact on liability to psychiatric illness. It will also result in biomarkers that signal risk in children early on and can be targeted by early preventions and interventions.

下丘脑-垂体-肾上腺（HPA）轴的激活是对应激的适应性反应。然而当 反复激活，可导致HPA轴失调。儿童时期的压力会改变生物系统， 调节HPA轴和免疫反应的基因表达以持续数十年的方式存在。 压力也与抑郁症和创伤后应激障碍的风险增加有关，这种风险会持续到成年， 两者都与自杀风险增加有关。然而，不同的神经内分泌特征 抑郁症中皮质醇增加和糖皮质激素受体（GR）反应性降低; PTSD中皮质醇减弱并GR反应性增强。炎症，也与压力有关， 据信是由于GR敏感性降低，可能是由于长期升高的皮质醇。然而 炎症与抑郁症和创伤后应激障碍有关，这是很难纠正的， GR反应性的差异模式。不一致的HPA轴轮廓也不符合高 这些疾病之间的共患病率。我们的首要目标是检查HPA轴的轨迹 和炎症途径;并确定生物轨迹，预测 适应不良的应激反应我们计划招募200名12-17岁的父母子女 在诊断（摄入）后3个月内被诊断为晚期癌症（压力），并在6岁时对其进行随访， 服用后18个月。这个群体将使我们能够研究压力反应的展开， 几乎不可能捕捉到其他压力源。我们还将招募并跟踪100名来自 其中父母或兄弟姐妹没有癌症或慢性疾病或死亡（对照组）。我们建议测量 HPA轴和炎症通路中的基因表达;测量毛发皮质醇浓度（HCC） 慢性HPA轴活动;唾液皮质醇以测量皮质醇觉醒反应（CAR）; GR敏感性; C- 反应蛋白和炎性细胞因子;并收集临床数据。我们假设在三个月内 父母诊断，压力儿童将显示HPA轴和炎症基因的表达增加， 与对照组相比，HCC、CAR和炎症标志物增加;但GR敏感性无差异。在 慢性应激反应中，应激儿童会表现出HPA轴基因表达下降，GR增强 与对照组相比，HCC和CAR随时间推移而降低。他们还将继续展示 增加炎症基因的表达和炎症。早期的生物反应及其 轨迹将预测抑郁症（抑郁症、创伤后应激障碍和自杀意念）和抑郁症的发作， 创伤后应激障碍;这些关系将受到预先存在的和正在进行的脆弱性和保护性的影响。 因素这项研究将促进我们对神经生物学、环境和行为的理解。 儿童压力反应的途径及其对精神疾病的影响。这还将招致 这些生物标志物可以在儿童早期发出风险信号，并可以通过早期预防和干预措施进行靶向治疗。