权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
7800244
负责人：
ANDREW H MILLER
金额：
$ 22.88万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7800244
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 PC12 Cells PTGS2 gene Pathway interactions Patients Peripheral Blood Mononuclear Cell Pheochromocytoma Phosphorylation Play 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 behavioral impairment brain tissue celecoxib 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(申请人提供)：许多疾病，包括自身免疫性、感染性和炎症性疾病，以及某些神经精神疾病，如重度抑郁症，都与对糖皮质激素的反应性降低有关。对糖皮质激素的反应性受损被认为是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过度活跃的原因，这可能导致行为改变。这一建议的主要假设是，慢性暴露于促炎细胞因子，如在慢性疾病和/或慢性应激的背景下，通过直接作用于糖皮质激素受体(GR)，导致糖皮质激素反应性受损。这项工作的长期目标是确定细胞因子影响GR信号的分子机制，并确定可能针对逆转细胞因子诱导的GR变化的特定信号分子/通路。在本项目中，提出了以下具体目标：1)确定促炎症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和促炎信号通路在GR调节中的相互作用；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，这些信号通路涉及丙型肝炎患者的GR信号、神经内分泌功能和情绪。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(AIMS 1和2)。检测IL-1和干扰素-α诱导的信号转导事件(包括激活p38、JNK和STAT以及NF-kB和COX信号通路)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活性降低的抑郁症患者的原代细胞(成纤维细胞)来检验PKA信号通路与IL-1和干扰素-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接受干扰素-α治疗之前和期间接受评估，并与15名等待接受干扰素治疗的丙型肝炎患者进行比较。干扰素-α是促炎细胞因子的有效激活剂，并因引起情绪改变而臭名昭著。将从接受干扰素治疗的患者的外周血中获取单个核细胞，用于评估p38、JNK和STAT以及NF-kB、STAT、COX-2和PKA信号转导。结果将与在一项检测情绪和体内糖皮质激素反应性测量(Dex-CRH测试)的配套研究中收集的数据相关联。总之，这些研究将有助于确定治疗内科疾病患者和内科健康患者情绪障碍的新靶点。