Neuroimmune Mechanisms of Glucocorticoid Resistance

糖皮质激素抵抗的神经免疫机制

基本信息

批准号：
7406095
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
项目类别：
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/7406095
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

项目摘要

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、感染性疾病和炎症性疾病以及某些神经精神疾病（例如重度抑郁症）与糖皮质激素反应性降低有关。人们认为，对糖皮质激素的反应性受损反过来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。该提议的主要假设是，在慢性疾病和/或慢性压力的情况下，长期接触促炎细胞因子可能会通过对糖皮质激素受体（GR）的直接影响而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，并确定可逆转细胞因子诱导的 GR 变化的特定信号分子/途径。在该项目中，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功能影响的信号转导途径，2）确定PKA和促炎信号传导途径在调节GR功能中的相互作用。 GR，3) 研究细胞内 p38、JNK、STAT 和 NF-kB 信号通路与 PKA 信号通路之间的关系，因为它们与 GR 信号传导、神经内分泌相关使用 IFN-a 治疗丙型肝炎的患者的功能和情绪。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 GR 功能信号转导事件（包括 p38、JNK 和 STAT 以及 NF-kB 和 COX 信号通路的激活）。在目标 2 中，这些研究将扩大到使用 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，在目标 3 中，将在 IFN-α 治疗之前和治疗期间对 30 名丙型肝炎患者进行评估，并与等待 IFN 治疗的 15 名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，因诱导情绪改变而臭名昭著。从接受 IFN-α 治疗的患者中获取外周血单核细胞，用于评估 p38、JNK 和 STAT 以及 NF-kB、STAT、COX-2 和 PKA 信号转导。结果将与检查情绪和体内糖皮质激素反应性测量（Dex-CRH 测试）的同伴研究中收集的数据相关联。总而言之，这些研究将有助于确定治疗患病和健康患者情绪障碍的新靶点。