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记物，这将提高我们对其风险架构以及诊断和治疗方法的了解，因为他们的公共卫生负担继续令人震惊地增长。自杀和自杀行为尤其如此，这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障碍的背景下，但相对较少的精神障碍受试者试图自杀。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通路之一。在这项R21先导性研究中，我们建议检测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，并将其与有自杀意念但以前没有自杀未遂史的精神病住院患者(n=35)和健康对照组(n=35)进行比较。肝细胞癌是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评估，因此将提供自杀未遂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研究首次将这一创新方法用于自杀行为。HPA轴调节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，在该模型中，我们将研究从HPA轴的基因表达和外周血中的炎症途径到肝癌、糖皮质激素受体(GR)敏感性、全身炎症水平(白介素6、C反应蛋白)、自杀行为的临床相关性和自杀行为。这项研究也首次研究了外周基因的表达以及HPA轴和炎症途径之间的关系与自杀行为的关系。我们假设，与其他两组相比，自杀未遂者GR表达减少，肝细胞癌增加，GR敏感性降低，炎症基因表达增加，炎症增加。这些生物措施将与睡眠障碍、冲动攻击性、情绪失调和降低的痛苦耐受性有关。生物学和临床措施将共同预测自杀行为。这项研究符合NIMH的研究领域标准(RDoC)，在该标准中，我们测量了自杀行为从正常到构思和企图的受试者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，该项目将检查肝癌的临床疗效，并在更大的样本中测试我们提出的自杀行为生物学途径的模型。实现这些目标将把检测高危个人的创新方法带到临床实践中，并将导致开发新的治疗方法，这将大大降低青年自杀行为导致的精神发病率和死亡率。

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.