Immune System & Genetic Modulation of Brain Development & Behavior in Adolescence

描述（由申请人提供）：免疫系统异常在几种精神疾病中反复被观察到，包括严重抑郁症、双相情感障碍和精神分裂症。然而，尚不清楚这些改变是这些疾病的潜在原因还是作为这些疾病的结果而发生。本研究将探讨炎症标志物在基因组成的调节下，在青少年发育期间，在精神疾病发作之前，对大脑功能和结构系统以及行为的调节中所起的作用。我们将对160名高风险青少年进行纵向研究，这些青少年的基线年龄在12至15岁之间，他们的父母被诊断患有抑郁症，但他们自己还没有被诊断出患有精神病。这些儿童将与一组年龄匹配的儿童（n=160）进行比较，这些儿童没有精神疾病家族史。我们将在五年内检查青少年的血液炎症标志物水平，并通过高密度基因分型技术将这些水平与涉及免疫系统的基因内的遗传变异联系起来，以评估基因构成在免疫信号传导中可能发挥的作用。同时，每个受试者将接受一系列的行为和生理评估，以评估精神疾病的几个潜在风险标记。这些评估包括：a)压力生活事件；B)精神症状和障碍的临床评估；C)行为/人格特征的维度测量，包括情绪、焦虑、冲动和敌意；d)功能和结构神经成像。在提交拨款时，已经收集并建立了320名青少年队列的基线神经影像学、DNA、血浆、淋巴细胞和永生化细胞系。在拟议的项目期间，青少年将每年重新评估一次，每两年重复两次神经成像协议。通过进行这些纵向研究，我们将能够确定免疫信号的变化是如何由基因组成调节的，并与关键发育时期的不利环境经历相结合，可能导致大脑发育和行为的变化，而这些变化反过来又可能导致疾病的发作。这些研究将有助于更好地了解炎症可能起重要作用的精神疾病的发育起源。这项研究的目的是研究在青少年发育时期参与炎症反应调节的基因，以便发现大脑发育和行为异常的早期迹象。反过来，细胞因子水平和遗传变异也将与行为和压力水平以及大脑结构和功能的关系进行检查。

DESCRIPTION (provided by applicant): Immune system abnormalities have been repeatedly observed in several psychiatric disorders, including severe depression, bipolar disorder and schizophrenia. However, it is not clear whether these alterations are an underlying cause or occur as a result of these disorders. The present study will investigate the role that inflammatory markers, as modulated by genetic make-up, play on regulation of functional and structural brain systems and behavior across the adolescent developmental period, prior to onset of psychiatric disorders. We will perform a longitudinal study of 160 high-risk adolescents, between the ages of 12 and 15 years at baseline, who have a parent diagnosed with depression, but who do not yet themselves have a psychiatric diagnosis. These children, will be compared to a cohort of age matched children (n=160) who have no family history of psychiatric disorders. We will examine blood levels of inflammatory markers in the adolescents throughout five years, and will correlate these levels with genetic variations within genes involved in the immune system, by using high-density genotyping techniques, to assess the role that genetic make-up may play in immune signaling. In parallel, each subject will undergo a series of behavioral and physiologic evaluations to assess several potential risk markers for psychiatric disorders. These evaluations include: a) stressful life events; b) clinical assessment of psychiatric symptoms and disorders; c) dimensional measures of behavior/personality traits including mood, anxiety, impulsivity and hostility; and d) functional and structural neuroimaging. At the time of the grant submission, baseline neuroimaging, DNA, plasma, lymphocytes, and immortalized cell lines have been collected and established in the cohort of 320 adolescents. During the proposed project period, adolescents will be reassessed yearly with the neuroimaging protocol being repeated twice at two year intervals. By performing these longitudinal studies, we will be able to identify how changes in immune signaling, as modulated by genetic make-up and in combination with exposure to adverse environmental experiences during a critical developmental period, may lead to changes in brain development and behavior which may in turn lead to disease onset. These studies will lead to a better understanding of the developmental origins of psychiatric disorders in which inflammation may play an important role. The goal of the study is to investigate genes involved in regulation of the inflammatory response during the adolescent developmental period, in order to detect early signs of abnormal brain development and behavior. In turn, cytokine levels and genetic variation will also be examined with relation to behavior and stress levels as well as brain structure and function.