Biomarkers in HPA axis and inflammatory pathways for 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，因为它们的公共卫生负担继续惊人地增长。自杀和自杀行为尤其如此，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，但相对较少的精神疾病受试者尝试自杀。下丘脑-垂体-肾上腺（HPA）轴失调被认为是应激、精神疾病和自杀行为之间的途径之一。在这项R21先导性研究中，我们建议检查头发皮质醇浓度（HCC）的精神科住院患者，13-25岁，承认自杀企图（n=35），并比较他们与精神科住院患者的自杀意念，但没有以前的历史企图（n=35）和健康对照组（n=35）。HCC是HPA轴慢性激活的标志物，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前皮质醇水平的评估。使用HPA轴测量的标准方法不可能进行这种时间评估。这项R21研究是第一次在自杀行为的背景下使用这种创新方法。HPA轴失调也影响炎症反应。我们提出了一个自杀行为的生物学途径的模型，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），自杀行为的临床表现和自杀行为。这项研究也是第一个研究外周基因表达和HPA轴和炎症途径与自杀行为之间的关系。我们假设，与其他两组相比，自杀者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。这些生物学测量将与增加的睡眠障碍、冲动性攻击、情绪失调和降低的痛苦耐受性相关。生物学和临床指标将共同预测自杀行为。本研究符合NIMH的研究领域标准（RDoC），我们正在测量受试者的负价系统的持续威胁结构，这些受试者处于从正常到构想和企图的自杀行为范围内。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，以检测高风险个体，并将导致新的治疗方法的发展，这将导致青年自杀行为导致的精神病发病率和死亡率显着降低。

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.