Adult Implications of Chronic Adolescent Stress: Mediators and Modifiers

描述（由申请人提供）：虽然压力是生活的一部分，但“有毒压力”的发生率在美国年轻人中正在增加。这种增加暴露于有毒水平的压力具有重大后果，并可能在整个成年期加速和加剧慢性精神和身体健康状况。虽然男性和女性都遭受早期生活压力的后果，但慢性发育压力的确切表现因性别而异。青春期的慢性压力尤其有害，因为压力源暴露与下丘脑-垂体-肾上腺（HPA）轴和生殖轴的成熟相互作用。这些内分泌轴的改变产生广泛的影响，因为这些轴的激素的许多受体是转录因子。这一系列研究的首要假设是，转录因子的调节和功能改变是青少年压力长期不利影响的基础。目前的应用集中在两个转录因子，我们的初步数据表明，慢性青春期应激改变：糖皮质激素受体（GR），一个转录因子，是HPA轴的主要效应子，和核因子κ轻链增强激活B细胞（NFκB），一个转录因子，介导炎症通路的激活。由于GR和NFκB之间存在显著的双向串扰，因此将这些转录因子一起考虑是有意义的。基于我们的初步数据，这个建议的中心假设是，慢性青春期应激导致成年女性GR为中心的修饰和成年男性NFκ B为中心的修饰。具体目标1的完成将确定青春期压力改变成年雄性和雌性大鼠GR调节的程度。这些数据将提供一个必要的了解青春期压力对GR调节的长期影响，这是必要的，以确定成年GR失调是否是一个候选机制，青春期压力引起的慢性疾病。具体目标2将检查青春期应激对成年雄性和雌性大鼠NFκB调节的影响。这些实验将提供有关青少年压力对成年期NFκB调节和易位的影响的信息，并确定NFκB在多大程度上是慢性青少年压力后过度炎症的候选调节因子。具体目标3将确定青少年压力在多大程度上改变成人 GR和NFκB B特异性介导的基因表达。这些数据与前两个目标是互补的，因为除了在易位水平上调节转录因子外，转录因子的作用可以在基因转录点上发散。总的来说，该应用程序生成的数据将确定慢性青少年应激诱导成人GR和NFκB变化的程度。拟议的工作将建立在机械水平上的慢性压力造成的性别差异的理解，并提供基础，制定临床实践的科学基础，允许更好地管理和消除与压力有关的疾病。

DESCRIPTION (provided by applicant): Although stress is part of life, the incidence of "toxic stress" is increasing among America's youth. This increased exposure to toxic levels of stress has substantial consequences and can precipitate and augment chronic mental and somatic health conditions throughout adulthood. While both men and women suffer the consequences of early life stress, the precise manifestation of chronic developmental stress varies in a sex-dependent manner. Chronic stress during adolescence is particularly harmful because of interactions of stressor exposure with the maturation the hypothalamic-pituitary-adrenal (HPA) axis and the reproductive axis. Alterations in these endocrine axes exert pervasive effects because many of the receptors for the hormones of these axes are transcription factors. The overarching hypothesis of this line of research is that altered regulation and function of transcription factors underlies the prolonged adverse effects of adolescent stress. The current application focuses on two transcription factors that our preliminary data suggest are altered by chronic adolescent stress: the glucocorticoid receptor (GR), a transcription factor that is the main effector of the HPA axis, and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), a transcription factor which mediates activation of inflammatory pathways. It is of interest to consider these transcription factors together because significant bidirectional crosstalk occurs between GR and NFκB. Based on our preliminary data, the central hypothesis of this proposal is that chronic adolescent stress leads to GR-centric modifications in adult females and NFκB-centric modifications in adult males. Completion of Specific Aim 1 will determine the extent to which adolescent stress alters regulation of the GR in adult male and female rats. These data will provide an essential understanding of the prolonged effects of adolescent stress on GR regulation which is necessary to determine whether adult GR dysregulation is a candidate mechanism for adolescent stress-induced chronic conditions. Specific Aim 2 will examine the influence of adolescent stress on regulation of NFκB in adult male and female rats. These experiments will provide information about the effects of adolescent stress on regulation and translocation of NFκB in adulthood and establish the degree to which NFκB is a candidate regulator of exaggerated inflammation following chronic adolescent stress. Specific Aim 3 will establish the extent to which adolescent stress alters adult gene expression specifically mediated by GR and NFκB. These data are complementary to the first two aims because in addition to regulation of transcription factors at the level of translocation, transcription factor effects can diverge at the point of gene transcription. Collectively, the data generated by this application will establish the extent to which chronic adolescent stress-induces changes in adult GR and NFκB. The proposed work will establish an understanding of sex differences created by chronic stress at the mechanistic level and provide the basis to develop a scientific foundation for clinical practice allowing for better management and elimination of stress-related disorders.