Neuroimmune Mechanisms of Glucocorticoid Resistance

描述（由申请人提供）：许多疾病，包括自身免疫性疾病、感染性疾病和炎症性疾病，以及某些神经精神疾病，如重度抑郁症，都与糖皮质激素反应性降低有关。对糖皮质激素的反应性受损反过来被认为会导致过度炎症以及促肾上腺皮质激素释放激素（CRH）和交感神经系统通路的过度活跃，这可能会导致行为改变。该建议的主要假设是，慢性疾病和/或慢性应激背景下可能发生的促炎细胞因子的慢性暴露通过直接影响糖皮质激素受体（GR）导致糖皮质激素反应性受损。拟议工作的长期目标是确定细胞因子影响GR信号传导的分子机制，并确定可能靶向逆转细胞因子诱导的GR变化的特定信号分子/途径。本项目提出以下具体目标：1)确定促炎细胞因子和其他免疫调节细胞因子对GR功能影响的信号转导通路，2)确定PKA与促炎信号通路在GR调控中的相互作用，3)研究细胞内p38、JNK、STAT、NF-kB信号通路与PKA信号通路在GR信号传导中的关系。为了实现这些目标，将在细胞系和原代细胞上进行一系列体外研究（目标1和目标2），研究il -1和ifn - α诱导的信号转导事件（包括p38、JNK、STAT以及NF-kB和COX信号通路的激活）对GR功能的影响。在Aim 2中，这些研究将扩展到使用PKA缺陷细胞系和来自PKA活性降低的抑郁症患者的原代细胞（成纤维细胞）来检查PKA信号通路与il -1和ifn - α诱导的信号通路的相互作用。最后，在Aim 3中，30名丙型肝炎患者将在IFN- α治疗前和治疗期间进行评估，并与15名等待IFN治疗的丙型肝炎患者进行比较。ifn - α是一种强效的促炎细胞因子激活剂，因诱导情绪改变而臭名昭著。将从ifn - α治疗的患者中获得外周血单个核细胞，用于评估p38、JNK和STAT以及NF-kB、STAT、COX-2和PKA信号。结果将与一项同伴研究中收集的数据相关联，该研究检查情绪和体内糖皮质激素反应性（Dex-CRH测试）。综上所述，这些研究将有助于确定治疗医学疾病和医学健康患者情绪障碍的新靶点。

DESCRIPTION (provided by applicant): A number of illnesses including autoimmune, infectious and inflammatory disorders as well as certain neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids. Impaired responsiveness to glucocorticpids in turn is believed to contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone (CRH) and sympathetic nervous system pathways, which may contribute to behavioral alterations. The primary hypothesis of this proposal is that chronic exposure to proinflammatory cytokines as may occur in the context of chronic medical illness and/or chronic stress leads to impaired glucocorticoid responsiveness through direct effects on the glucocorticoid receptor (GR). The long-term objectives of the proposed work are to determine the molecular mechanisms by which cytokines influence GR signaling and to identify specific signaling molecules/pathways that may be targeted to reverse cytokine-induced GR changes. In this project, the following specific aims are proposed: 1) to determine the signal transduction pathways that mediate the effects of proinflammatory cytokines and other immunoregulatory cytokines on GR function, 2) to determine the interaction of PKA and proinflammatory signaling pathways in the regulation of GR, and 3) to investigate the relationship between intracellular p38, JNK, STAT, and NF-kB signaling pathways and PKA signaling pathways as they relate to GR signaling, neuroendocrine function and mood in patients treated with IFN-a for hepatitis C. To accomplish these aims, a series of in vitro studies (Aims 1 and 2) will be conducted on cell lines and primary cells, examining the impact of IL-1-and IFN-alpha-induced signal transduction events (including activation of p38, JNK, and STAT as well as NF-kB and COX signaling pathways) on GR function. In Aim 2, these studies will be expanded to examine the interaction of PKA signaling pathways with IL-1-and IFN-alpha-induced signaling pathways using PKA deficient cell lines and primary cells (fibroblasts) from depressed patients with reduced PKA activity. Finally, in Aim 3, 30 patients with hepatitis C will be assessed before and during IFN-alpha treatment and compared to 15 hepatitis C patients awaiting IFN therapy. IFN-alpha is a potent activator of proinflammatory cytokines and is notorious for inducing mood alterations. Peripheral blood mononuclear cells will be obtained from IFN-alpha-treated patients for the assessment of p38, JNK, and STAT as well as NF-kB, STAT, COX-2 and PKA signaling. Results will be correlated with data being collected in a companion study examining mood and in vivo measures of glucocorticoid responsiveness (Dex-CRH test). Taken together, these studies will help identify novel targets for the treatment of mood disorders in both medically ill and medically healthy patients.