Neuroimmune Mechanisms of Glucocorticoid Resistance

糖皮质激素抵抗的神经免疫机制

• 批准号: 7218705
• 负责人: ANDREW H MILLER
• 金额: $ 19.61万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-05 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218705
• 关键词: Antisense Oligonucleotides; Autoimmune Process; Autopsy; Behavior; Behavioral; Binding; Biochemical; Biological; Biological Assay; Biological Models; Cell Line; Cells; Chronic; Chronic stress; Companions; Control Groups; Corticotropin-Releasing Hormone; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytokine Signaling; DNA; DNA Binding; Data; Depressed mood; Development; Disease; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Event; Exhibits; Exposure to; Feedback; Fibroblasts; Functional disorder; Glioma; Glucocorticoid Receptor; Glucocorticoids; Hepatitis C; Hippocampus (Brain); Hyperactive behavior; Immune response; Immune system; Impairment; In Vitro; Inflammation; Inflammatory; Interferon-alpha; Interferons; Interleukin-1; Interleukin-1 alpha; Lead; Left; Ligand Binding; Luciferases; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Medical; Mental Depression; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mood Disorders; Moods; Mus; NF-kappa B; NFKB Signaling Pathway; Neuroimmunomodulation; Neurons; Neurosecretory Systems; Nuclear; Nuclear Translocation; Numbers; PC12 Cells; PTGS2 gene; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Pheochromocytoma; Phosphorylation; Play; Polymerase Chain Reaction; Prostaglandin-Endoperoxide Synthase; Rattus; Receptor Signaling; Regulation; Research; Research Personnel; Resistance; Role; STAT5A gene; Sampling; Secondary to; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Skin; Sympathetic Nervous System; Techniques; Testing; Therapeutic; Time; Transfection; Western Blotting; Work; brain tissue; celecoxib; cyclooxygenase 1; cyclooxygenase 2; cytokine; design; disturbance in affect; environmental stressor; glucocorticoid-induced orphan receptor; in vivo; inhibitor/antagonist; neuropsychiatry; novel; programs; protein protein interaction; receptor expression; receptor function; research study; response; transcription factor

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.

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进而被认为有助于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，这可能有助于行为改变。该建议的主要假设是，慢性暴露于促炎细胞因子，如在慢性医学疾病和/或慢性应激的背景下可能发生的，通过对糖皮质激素受体（GR）的直接作用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甜菜碱诱导的GR变化的特定信号传导分子/途径。在这个项目中，提出了以下具体目标：1）确定介导促炎细胞因子和其他免疫调节细胞因子对GR功能的影响的信号转导途径，2）确定PKA和促炎信号转导途径在GR调节中的相互作用，和3）研究细胞内p38、JNK、STAT、以及NF-κ B信号通路和PKA信号通路，因为它们与用IFN-α治疗丙型肝炎的患者的GR信号传导、神经内分泌功能和情绪有关。为了实现这些目标，将对细胞系和原代细胞进行一系列体外研究（目标1和2），检查IL-1和IFN-α诱导的信号转导事件（包括p38、JNK和STAT以及NF-kB和考克斯信号通路的激活）对GR功能的影响。在目标2中，这些研究将扩展到使用PKA缺陷细胞系和来自PKA活性降低的抑郁患者的原代细胞（成纤维细胞）来检查PKA信号传导途径与IL-1和IFN-α诱导的信号传导途径的相互作用。最后，在目标3中，将在IFN-α治疗之前和期间评估30名丙型肝炎患者，并与15名等待IFN治疗的丙型肝炎患者进行比较。IFN-α是促炎细胞因子的有效激活剂，并且因诱导情绪改变而臭名昭著。将从IFN-α治疗的患者获得外周血单核细胞，用于评估p38、JNK和STAT以及NF-κ B、STAT、考克斯-2和PKA信号传导。结果将与在检查情绪和糖皮质激素反应性的体内测量（Dex-CRH测试）的伴随研究中收集的数据相关。总之，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。