Adult Implications of Chronic Adolescent Stress: Mediators and Modifiers

描述(申请人提供)：尽管压力是生活的一部分，但在美国年轻人中，“有毒压力”的发生率正在增加。这种暴露在有毒水平的压力下会产生实质性的后果，并可能在整个成年期加速和加剧慢性精神和躯体健康状况。虽然男性和女性都会遭受早年生活压力的后果，但慢性发展压力的确切表现因性别而异。青春期的慢性应激尤其有害，因为应激源暴露与成熟的下丘脑-垂体-肾上腺(HPA)轴和生殖轴相互作用。这些内分泌轴的变化产生了普遍的影响，因为这些轴的激素受体中的许多都是转录因子。这一系列研究的主要假设是，转录因子的调节和功能改变是青春期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：糖皮质激素受体(GR)，HPA轴的主要效应因子，以及核因子-kappa-轻链-活化B细胞增强子(NF？B)，它是一种介导炎症途径激活的转录因子，我们的初步数据表明，这两种转录因子可被慢性青春期应激改变。将这些转录因子放在一起考虑是有意义的，因为GR和NF？B之间存在显著的双向串扰。根据我们的初步数据，这一假设的中心假设是，慢性青春期应激导致成年女性以GR为中心的修饰，成年男性以NF？B为中心的修饰。具体目标1的完成将决定青春期应激在多大程度上改变成年雄性和雌性大鼠GR的调节。这些数据将提供对青少年应激对GR调节的长期影响的基本理解，这对于确定成人GR调节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。特定目的2将研究青春期应激对成年雄性和雌性大鼠核因子？B调节的影响。这些实验将提供有关青春期应激对成年后核因子B调节和移位的影响的信息，并确定核因子B在多大程度上是慢性青春期应激后过度炎症的候选调节因子。具体目标3将确定青春期压力改变成人的程度 这些数据与前两个目的是互补的，因为除了转录因子在易位水平上的调节外，转录因子的作用在基因转录水平上可能会有所不同。总而言之，这项应用产生的数据将确定慢性青春期应激在多大程度上导致成人GR和NF？B的变化。拟议的工作将在机制水平上建立对慢性应激造成的性别差异的理解，并为临床实践提供科学基础，从而更好地管理和消除应激相关障碍。

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 (NF?B), 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 NF?B. 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 NF?B-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 NF?B in adult male and female rats. These experiments will provide information about the effects of adolescent stress on regulation and translocation of NF?B in adulthood and establish the degree to which NF?B 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 NF?B. 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 NF?B. 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.