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）轴的激活是对压力的适应性反应。然而,当