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

基本信息

批准号：
9896866
负责人：
Nadine M. Melhem
金额：
$ 64.71万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/9896866
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 Development Diagnosis Disease Family Feasibility Studies Feeling suicidal Gene Expression Genes Glucocorticoid Receptor Goals Hair Hydrocortisone Hyperactive behavior Immune response Incidence Inflammation Inflammatory Infrastructure 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 Risk Salivary Siblings Signal Transduction Stress Suicide TNF gene Target Populations Time aged biological adaptation to stress biological systems cancer diagnosis childhood adversity comorbidity 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

项目摘要

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) 轴的激活是对压力的适应性反应。然而，当反复激活，会导致 HPA 轴失调。童年时期的压力会改变生物系统以持续数十年的方式调节 HPA 轴和免疫反应的基因表达。压力还与抑郁症和创伤后应激障碍 (PTSD) 的风险增加有关，这种风险会持续到成年期，两者都与自杀风险增加有关。然而，不同的神经内分泌特征是抑郁症患者皮质醇增加，糖皮质激素受体 (GR) 反应性降低；和减弱皮质醇并增强 PTSD 中的 GR 反应性。炎症也与压力有关据信这是由于 GR 敏感性降低造成的，可能是皮质醇长期升高的结果。然而炎症与抑郁症和创伤后应激障碍 (PTSD) 都相关，但由于其明显的症状很难纠正 GR 反应性的差异模式。不一致的 HPA 轴轮廓也不符合高要求这些疾病之间的共病率。我们的首要目标是检查 HPA 轴的轨迹以及儿童应对压力的炎症途径；并确定预测的生物轨迹适应不良的应激反应。我们拟新招募200名12-17岁父母子女在诊断（摄入）后 3 个月内诊断出患有晚期癌症（压力），并在 6 点和 6 点进行随访摄入后18个月。这个群体将使我们能够研究压力反应的展开，即几乎不可能捕捉到其他压力源。我们还将招募并跟踪 100 名来自家庭的孩子父母或兄弟姐妹没有患有癌症或慢性疾病或死亡（对照）。我们建议测量 HPA 轴和炎症通路中的基因表达；头发皮质醇浓度 (HCC) 测量慢性 HPA 轴活动；唾液皮质醇测量皮质醇觉醒反应（CAR）； GR 灵敏度； C- 反应蛋白和炎症细胞因子；并收集临床数据。我们假设 3 个月内父母诊断，应激儿童会表现出 HPA 轴和炎症基因表达增加，与对照组相比，HCC、CAR 和炎症标志物增加；但 GR 敏感性没有差异。在对慢性应激的反应，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，敏感性随着时间的推移 HCC 和 CAR 降低。他们还将继续展现炎症基因和炎症表达增加。早期的生物反应及其轨迹将预测症状（抑郁症、创伤后应激障碍和自杀意念）以及抑郁症的发作创伤后应激障碍；这些关系将受到先前存在和持续存在的脆弱性和保护性的影响因素。这项研究将增进我们对神经生物学、环境和行为的理解儿童应激反应的途径及其对精神疾病的影响。这也将导致早期发出儿童风险信号的生物标志物，可以作为早期预防和干预的目标。