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”在美国年轻人中的发病率正在上升。这种暴露于有毒压力水平的增加会产生严重后果，并可能在整个成年期引发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在性别依赖的方式上有所不同。由于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，青春期的慢性压力尤其有害。这些内分泌轴的改变会产生普遍影响，因为这些轴上的激素的许多受体是转录因子。这一研究的首要假设是，转录因子的调节和功能的改变是青少年压力长期不利影响的基础。目前的应用主要集中在两种转录因子上，我们的初步数据表明慢性青少年压力会改变它们：糖皮质激素受体（GR），一种转录因子，是HPA轴的主要效应因子，以及活化B细胞的核因子kappa-轻链增强因子（NFκB），一种介导炎症通路激活的转录因子。将这些转录因子放在一起考虑是很有趣的，因为GR和NFκB之间存在显著的双向串扰。根据我们的初步数据，本研究的中心假设是，青少年慢性应激导致成年女性以gr为中心的改变和成年男性以nf κ b为中心的改变。具体目标1的完成将确定青春期应激在多大程度上改变成年雄性和雌性大鼠的GR调节。这些数据将为青少年应激对GR调节的长期影响提供必要的理解，这对于确定成人GR失调是否是青少年应激诱导的慢性疾病的候选机制是必要的。特异性目的2将研究青春期应激对成年雄性和雌性大鼠NFκB调节的影响。这些实验将提供青少年应激对成年期NFκB调控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应激后夸大炎症的候选调节因子。具体目标3将确定青少年压力改变成人的程度

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.