Biomarkers in HPA axis and inflammatory pathways for suicidal behavior in youth

HPA 轴的生物标志物和青少年自杀行为的炎症通路

基本信息

批准号：
8561479
负责人：
Nadine M. Melhem
金额：
$ 22.88万
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：
2013
资助国家：
美国
起止时间：
2013-08-29 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8561479
关键词：
Acute Adolescent Adrenal Glands Affect Age-Years Aggressive behavior Alcohol abuse Antidepressive Agents Architecture Biological Biological Markers Biological Models Bipolar Disorder C-reactive protein Cause of Death Characteristics Chronic Chronic stress Clinical Development Diagnosis Disease susceptibility Down-Regulation Emotions Exposure to Feeling suicidal Future Gene Expression Genes Glucocorticoid Receptor Goals Hair Hydrocortisone Hyperactive behavior Hypothalamic structure Individual Inflammation Inflammatory Inflammatory Response Inpatients Interleukin-1 Interleukin-2 Interleukin-6 Interleukin-8 Lead Measurement Measures Medicine Mental disorders Methods Modeling Molecular Profiling Mood Disorders Morbidity - disease rate NF-kappa B Pathogenesis Pathway interactions Patients Peripheral Personality Disorders Physiological Pilot Projects Pituitary Gland Post-Traumatic Stress Disorders Prevention Public Health Recording of previous events Research Risk Role Sampling Schizophrenia Sleep disturbances Staging Stress Substance abuse problem Suicide Suicide attempt System TNF gene Testing Time Tissue-Specific Gene Expression Youth behavior measurement clinical efficacy clinical practice distress tolerance drug discovery high risk hypothalamic-pituitary-adrenal axis ideation improved innovation insight mortality peripheral blood psychosocial public health relevance receptor expression receptor sensitivity response stressor suicidal suicidal behavior suicide attempter suicide brain young adult

项目摘要

DESCRIPTION (provided by applicant): There is a pressing need to detect biological signatures, or biomarkers, for psychiatric diseases that will improve our understanding of their architecture of risk and methods of diagnosis and treatment, as their public health burden continues to grow alarmingly. This is especially true for suicide and suicidal behavior, the most serious sequelae of psychiatric diseases and the 3rd leading cause of death among adolescents and young adults. While suicidal behavior occurs in the context of psychiatric disorders, relatively few subjects with psychiatric disorders attempt suicide. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is postulated as one of the pathways between stress, psychiatric diseases, and suicidal behavior. In this R21 pilot study, we propose to examine hair cortisol concentrations (HCC) in psychiatric inpatients, 13-25 years of age, admitted for suicide attempt (n=35) and compare them to psychiatric inpatients with suicidal ideation but no previous history of attempts (n=35) and healthy controls (n=35). HCC is a marker of chronic activation of the HPA axis as it provides a retrospective assessment of cortisol levels over the past few months and thus will provide an assessment of cortisol levels prior to suicide attempt. This temporal assessment is not possible using standard methods of HPA axis measurement. This R21 study is the first to use this innovative method in the context of suicidal behavior. HPA axis dysregulation also affects the inflammatory response. We propose a model for the biological pathways to suicidal behavior where we will examine the pathways from gene expression in the HPA axis and inflammatory pathways in peripheral blood to HCC, glucocorticoid receptor (GR) sensitivity, systemic levels of inflammation (Interleukin-6, C-reactive protein), clinical correlats of suicidal behavior, and suicidal behavior. This study is also the first to examine peripheral gene expression and the relationship between the HPA axis and inflammatory pathways in relation to suicidal behavior. We hypothesize that suicide attempters will have decreased GR expression, increased HCC, decreased GR sensitivity, increased expression of inflammatory genes, and increased inflammation as compared to the other two groups. These biological measures will be associated with increased sleep disturbances, impulsive aggression, emotion dysregulation, and reduced distress tolerance. Biological and clinical measures will together predict suicidal behavior. This study is in line with NIMH's Research Domain Criteria (RDoC) where we are measuring the sustained threat construct of the negative valence systems in subjects who are on the spectrum of suicidal behavior from normal to ideation and attempt. This R21 study is the first exploratory stage of a future project that will examine the clinical efficac of HCC and test our proposed model for the biological pathways of suicidal behavior in larger samples. Achieving these goals will bring innovative methods to clinical practice to detect individuals at high risk and will result in the development of new treatment approaches, which will both lead to a significant reduction in psychiatric morbidity and mortality resulting from suicidal behavior in youth.

描述（由申请人提供）：迫切需要检测精神疾病的生物特征或生物标志物，这将提高我们对其风险结构以及诊断和治疗方法的理解，因为其公共卫生负担持续惊人地增长。对于自杀和自杀行为来说尤其如此，自杀和自杀行为是精神疾病最严重的后遗症，也是青少年和年轻人死亡的第三大原因。虽然自杀行为发生在精神疾病的背景下，但患有精神疾病的受试者相对较少尝试自杀。下丘脑-垂体-肾上腺（HPA）轴失调被认为是压力、精神疾病和自杀行为之间的途径之一。在这项 R21 试点研究中，我们建议检查 13-25 岁因自杀未遂入院的精神病住院患者 (n=35) 的头发皮质醇浓度 (HCC)，并将其与有自杀意念但既往无自杀史的精神病住院患者进行比较。尝试（n=35）和健康对照（n=35）。 HCC 是 HPA 轴慢性激活的标志，因为它提供了过去几个月皮质醇水平的回顾性评估，因此将提供自杀企图之前皮质醇水平的评估。使用 HPA 轴测量的标准方法无法进行这种时间评估。这项 R21 研究首次在自杀行为的背景下使用这种创新方法。 HPA 轴失调也会影响炎症反应。我们提出了一个自杀行为的生物学途径模型，我们将检查从 HPA 轴中的基因表达和外周血中的炎症途径到 HCC 的途径、糖皮质激素受体 (GR) 敏感性、全身炎症水平（白细胞介素 6、C -反应蛋白），自杀行为的临床相关性和自杀行为。这项研究也是第一个检查外周基因表达以及 HPA 轴和炎症通路与自杀行为相关的关系的研究。我们假设，与其他两组相比，自杀未遂者的 GR 表达降低，HCC 增加，GR 敏感性降低，炎症基因表达增加，炎症增加。这些生物学指标与睡眠障碍增加、冲动攻击、情绪失调和痛苦耐受力降低有关。生物学和临床测量将共同预测自杀行为。这项研究符合 NIMH 的研究领域标准 (RDoC)，我们正在测量处于从正常自杀行为到意念和企图自杀行为范围内的受试者的负价系统的持续威胁结构。这项 R21 研究是未来项目的第一个探索阶段，该项目将检查 HCC 的临床疗效，并在更大的样本中测试我们提出的自杀行为生物学途径模型。实现这些目标将为临床实践带来创新方法，以检测高危个体，并将导致新治疗方法的开发，这将显着降低青少年自杀行为导致的精神疾病发病率和死亡率。