Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

神经内分泌应激反应在炎症和行为疾病中的作用。

• 批准号: 7969307
• 负责人: ESTHER M. STERNBERG
• 金额: $ 217.71万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969307
• 关键词: Accounting; Affect; Animal Model; Antigens; Anxiety; Area; Bacterial Toxins; Behavior; Behavior Disorders; Behavior Therapy; Behavioral; Biological Markers; Blood; Brazil; Calcitonin Gene-Related Peptide; Cancer Survivor; Cardiovascular Diseases; Cell physiology; Cell surface; Cells; Child; Clinical; Clinical Protocols; Clinical Research; Clostridium difficile; Clostridium sordellii lethal toxin LT; Collaborations; Collection; Dendritic Cells; Depressive disorder; Diabetes Mellitus; Diagnostic; Disease; Early treatment; Elderly; Epidemiology; Estrus; Extramural Activities; Female; Functional disorder; Future; Gene Targeting; Glucocorticoid Receptor; Glucocorticoids; Goals; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Host Defense; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory; Institutes; Integration Host Factors; Knowledge; Lasers; Lead; Life Cycle Stages; Light; Longevity; MALDI-TOF Mass Spectrometry; Major Depressive Disorder; Mass Spectrum Analysis; Measures; Mediating; Methodology; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Profiling; Molecular Target; Mood Disorders; Moods; National Center for Complementary and Alternative Medicine; National Institute of Mental Health; Neuropeptides; Neurosecretory Systems; Nuclear Hormone Receptors; Osteoporosis; Pain; Pathway interactions; Patient Monitoring; Pattern; Persons; Physiological; Plasma; Play; Post-Translational Protein Processing; Postdoctoral Fellow; Predisposition; Pregnancy; Pregnant Women; Production; Progesterone; Progesterone Receptors; Protocols documentation; Recycling; Regulation; Repression; Research; Research Ethics Committees; Resistance; Risk; Rodent; Role; Sensory; Substance P; Sweat; Sweating; System; T-Cell Proliferation; Tai Ji; Technology; Therapeutic; Time; Tissues; Toxin; Translational Research; Treatment Protocols; United States National Institutes of Health; Universities; Vasoactive Intestinal Peptide; Vulnerable Populations; Women' s Group; Women' s Role; Work; Workplace; anthrax lethal factor; biological adaptation to stress; chemokine receptor; clinical remission; cytokine; depression; depressive symptoms; disturbance in affect; glucocorticoid-induced orphan receptor; immunoaffinity chromatography; in vivo; infliximab; ionization; neuropeptide Y; novel; prognostic; promoter; receptor; receptor expression; receptor function; relating to nervous system; response; tool; transcription factor; uptake

PROJECT I. Sweat Patch Biomarkers: Clinical Studies. In FY 2009, we showed that neural and immune biomarkers are detectable in sweat and strongly correlate with plasma levels in a group of women with major depressive disorder (MDD) in clinical remission (5). Specifically, pro-inflammatory cytokines were elevated, as was the sympathetic neuropeptide neuropeptide Y (NPY) and the sensory/pain-related neuropeptides, substance P (SP) and CGRP (calcitonin gene-related peptide), while the parasympathetic neuropeptide vasoactive intestinal polypeptide (VIP) was significantly decreased. This pattern is consistent with a shift in MDD from parasympathetic to sympathetic tone, and an underlying pro-inflammatory state that could account for enhanced susceptibility to conditions known to be co-morbidly expressed with MDD, including cardiovascular disease, osteoporosis and diabetes. Moreover, biomarker levels strongly correlated with symptoms of depression and anxiety, indicating functional significance of these biomarker profiles. In order to determine the extent to which particular biomarker profiles reflect specific diseases or a state of health, in FY09 we are applying sweat patch biomarkers in five ongoing IRB approved clinical protocols in collaboration with other NIH institutes and extramural insitutions, including: (i) Emory University TRD-Infliximab Study. (Emory University IRB 00011734, NIMH OHSR Exemption #4025); (ii) Brazil - OCD Study (NIH protocol IRB 3737); (iii) Emory/CDC CFS Study (Emory University IRB 000551-2005, NIMH OHSR Exemption #4026); (iv) NCCAM - Tai Chi/Cancer Survivor Study (NCI protocol #06-AT-0016); (v) GSA - Work Environment Study (NIA IRB 2003-142). Project II Summary: Animal Models of Glucocorticoid Resistance, Inflammation and Behavior: In our studies evaluating the effects of progesterone on immune cell (dendritic cell, DC) function and maturation and the role of female sex hormones in host defense, we found that progesterone in non-pregnancy-associated concentrations and through a progesterone receptor (PR)-mediated mechanism suppresses mature DC production of pro-inflammatory cytokines, cell surface marker expression (co-stimulatory molecules and chemokine receptors) and stimulation of T cell proliferation, but has little effect on immature DC antigen uptake (2-4). These effects, which are comparable to those of glucocorticoids on DC function, indicate that progesterone plays an important role in regulation of innate and adaptive immunity in females. In FY09 we found that progesterone effects on DC function vary throughout the rodent estrus cycle and are dependent on PR expression, which varies throughout the cycle in vitro and in vivo, and also differentially affects DCs from different tissues. This indicates that females immune responses vary physiologically throughout the estrus cycle, and has important implications for clinical susceptibility to infection and inflammation during the cycle and during pregnancy. Such physiological fluctuations in hormone status could also impact cellular responses that play a role in mood. Since cytokines are known to affect mood, and may play a role in some forms of depression as well as in mood alterations in sickness behavior, factors such as progesterone, which alter cytokine production by cells could contribute to differential mood disorder susceptibilities in females throughout the life cycle. In our bacterial toxin studies we identified bacterial toxins that through inactivation of the MAPK (mitogen-activated protein kinase), pathways, induce partial repression of nuclear hormone receptors (NHRs), including GR and PR (8). These toxins include Bacillus anthracis lethal toxin (LeTx), Clostridium sordellii lethal toxin (TcsL) and the C. difficile toxins, toxin A (TcdA) and B (TcdB). Our studies in FY09 indicate that bacterial toxin NHR repression is both receptor and promoter-dependent and is associated with the repression of other transcription factors (6). Preliminary evidence suggests that the toxins' effects are mediated through post-translational modifications to GR. These toxins could provide a tool to study the effects of induced glucocorticoid resistance on a variety of physiological systems.

项目I.汗斑生物标志物：临床研究。在2009财年，我们发现神经和免疫生物标志物可在汗液中检测到，并且与一组临床缓解期重度抑郁症（MDD）女性的血浆水平密切相关（5）。具体来说，促炎细胞因子升高，交感神经肽神经肽Y（NPY）和感觉/疼痛相关神经肽P物质（SP）和CGRP（降钙素基因相关肽）也升高，而副交感神经肽血管活性肠肽（VIP）显着减少。这种模式与MDD从副交感神经紧张到交感神经紧张的转变以及潜在的促炎状态一致，这可能导致对已知与MDD共病表达的疾病（包括心血管疾病、骨质疏松症和糖尿病）的易感性增强。此外，生物标志物水平与抑郁和焦虑症状密切相关，表明这些生物标志物谱的功能意义。为了确定特定生物标志物谱反映特定疾病或健康状态的程度，在2009财年，我们与其他NIH研究所和校外研究所合作，将汗斑生物标志物应用于五项正在进行的IRB批准的临床方案中，包括：（i）埃默里大学TRD-英夫利昔单抗研究。（Emory University IRB 00011734，NIMH OHSR豁免#4025）;（ii）巴西- OCD研究（NIH方案IRB 3737）;（iii）Emory/CDC CFS研究（Emory University IRB 000551-2005，NIMH OHSR豁免#4026）;（iv）NCCAM -太极/癌症幸存者研究（NCI方案#06-AT-0016）; GSA ----工作环境研究（NIA IRB 2003-142）。 项目II摘要：糖皮质激素抵抗、炎症和行为的动物模型：在我们的研究中，评估了孕酮对免疫细胞的影响，（树突状细胞，DC）的功能和成熟以及雌性性激素在宿主防御中的作用，我们发现孕酮在非妊娠相关浓度下并通过孕酮受体（PR）介导的机制抑制成熟DC产生促炎细胞因子，细胞表面标志物表达（共刺激分子和趋化因子受体）和刺激T细胞增殖，但对未成熟DC抗原摄取几乎没有影响（2-4）。这些效果，这是可比的糖皮质激素对DC功能，表明孕酮在调节女性的先天性和适应性免疫中起着重要的作用。在FY 09中，我们发现孕酮对DC功能的影响在整个啮齿动物发情周期中变化，并且依赖于PR表达，PR表达在体外和体内的整个周期中变化，并且还对来自不同组织的DC产生差异性影响。这表明，女性的免疫反应在整个发情周期的生理变化，并在周期和怀孕期间的感染和炎症的临床易感性具有重要意义。激素状态的这种生理波动也可能影响在情绪中发挥作用的细胞反应。由于已知细胞因子会影响情绪，并且可能在某些形式的抑郁症以及疾病行为的情绪改变中发挥作用，因此改变细胞产生细胞因子的因素如孕酮可能有助于女性在整个生命周期中的不同情绪障碍易感性。在我们的细菌毒素研究中，我们鉴定了通过MAPK（促分裂原活化蛋白激酶）途径失活诱导部分抑制核激素受体（NHR）（包括GR和PR）的细菌毒素（8）。这些毒素包括炭疽杆菌致死毒素（LeTx）、索氏梭菌致死毒素（TcsL）和C.艰难梭菌毒素，毒素A（TcdA）和毒素B（TcdB）。我们在FY 09中的研究表明，细菌毒素NHR抑制是受体和启动子依赖性的，并与其他转录因子的抑制有关（6）。初步证据表明，毒素的影响是通过翻译后修饰GR介导的。这些毒素可以提供一种工具来研究诱导的糖皮质激素抵抗对各种生理系统的影响。