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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。

基本信息

批准号：
8556911
负责人：
ESTHER M. STERNBERG
金额：
$ 152.78万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/8556911
关键词：
Accounting Address Affect Agreement Animal Model Animals Antibodies Antigens Anxiety Area Ascaridil Award Behavior Behavior Disorders Behavior Therapy Behavioral Biological Markers Blood Bone Marrow Brain Brazil CD4 Positive T Lymphocytes Calcitonin Gene-Related Peptide Cancer Survivor Cardiovascular Diseases Cell physiology Cell surface Cells Centers for Disease Control and Prevention (U.S.)Circadian Rhythms Clinical Clinical Protocols Clinical Research Clinical Treatment Collaborations Collection Data Dendritic Cells Depressive disorder Diabetes Mellitus Diagnostic Disease Environment Epidemiology Estrous Cycle Exercise Extramural Activities Female Functional disorder Funding Glass Glucocorticoid Receptor Glucocorticoids Goals Health Heating Helper-Inducer T-Lymphocyte Hormonal Hormones Host Defense Hydrocortisone Immune Immune response Immune system In Vitro Individual Infection Inflammation Inflammatory Institutes Institution Institutional Review Boards Integration Host Factors Intervention Kidney Knowledge Lasers Lead Life Cycle Stages Liver Longevity Lymphoid Lymphoid Tissue Major Depressive Disorder Mass Spectrum Analysis Measures Mediating Menstrual cycle Mental Depression Methodology Methods Molecular Classification of Tumors Molecular Profiling Molecular Target Monitor Mood Disorders Moods Mus Nanotechnology National Center for Complementary and Alternative Medicine National Institute of Mental Health Natural Immunity Neuropeptides Neurosciences Neurosecretory Systems Osteoporosis Pain Pathogenesis Patient Monitoring Pattern Persons Physiological Plasma Play Post-Traumatic Stress Disorders Postdoctoral Fellow Predisposition Pregnancy Production Progesterone Progesterone Receptors Protocols documentation Recording of previous events Recovery Recycling Regenerative Medicine Regulation Reporting Research Resistance Risk Rodent Role Salivary Sensory Severities Spleen Staging Stress Substance P Sweat Sweating Symptoms T-Cell Proliferation Tai Ji Technology Testing Therapeutic Effect Thymus Gland Time Tissues Transgenic Animals Translational Research Traumatic Brain Injury United States National Institutes of Health Universities Uterus Variant Vasoactive Intestinal Peptide Virus Diseases War West Nile virus Wild Type Mouse Woman Women&apos s Group Workplace adaptive immunity biological adaptation to stress cell motility chemokine receptor clinical remission cytokine depressive symptoms disturbance in affect heart rate variability immunoaffinity chromatography in vivo infliximab intraperitoneal ionization mouse model neuropeptide Y prognostic receptor expression receptor function relating to nervous system response steroid hormone tool uptake

项目摘要

PROJECT I. Sweat Patch Biomarkers: Clinical Studies. This is currently the main focus of the SNIB. We previously 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 (Marques-Deak, 2006, J Immunol Methods; Cizza 2008, Biol Psych). 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 FY11 we are continuing to apply sweat patches in five ongoing IRB approved clinical protocols in collaboration with other NIH institutes and extramural institutions, 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). Results of study (v), (GSA Workplace Study) indicate that physical features of the workplace environment are associated with altered measures of the physiological stress response, as indicated by a greater rise in salivary cortisol upon awakening and flatter circadian variation of heart rate variability in subjects occupying old office space compared to those in new office space (Thayer et al. 2010 Eur J Cardiovasc Prev Rehabil). Our current studies focus on transitioning to a more high-throughput static antibody glass chip microarray platform and developing a better patch using nanotechnology. In FY10-11 the SNIB obtained funding support for this project through an NIH Directors Challenge Award in partnership with the NCCAM Director; NCCAM; the Center for Neuroscience and Regenerative Medicine (CNRM)/USUHS/DoD/NIH); and NIMH IRP funds. Project II Summary: Animal Models of Glucocorticoid Resistance, Inflammation and Behavior: In our studies evaluating the effects of the steroid hormone progesterone on immune cell (dendritic cell, DC) function, activation, and the role in inflammation and host defense, we assessed DCs from lymphoid (spleen, bone marrow, thymus) and non-lymphoid (liver, kidney, uterus) tissues. Our results show that progesterone in non-pregnancy-associated concentrations and through a progesterone receptor (PR)-mediated mechanism suppresses mature DC production of pro-inflammatory and helper T cell-related cytokines, cell surface marker expression (co-stimulatory molecules and chemokine receptors), cellular migration/motility, and stimulation of T cell proliferation but has little effect on immature DC antigen uptake (Butts et al. 2009 Methods Mol Biol; Butts et al. 2010 Mucosal Immunol). 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. We also found that progesterone effects on DC function vary throughout the rodent estrous cycle and are dependent on PR expression, which varies throughout the cycle in vitro and in vivo with intravaginal and intraperitoneal administration. This indicates that females' immune responses vary physiologically throughout the estrous cycle and has important implications for clinical susceptibility to infection and inflammation throughout 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. Furthermore, progesterone has been shown to have beneficial therapeutic effects in traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). As such this data is important in understanding the pathogenesis and specific clinical conditions in which progesterone may be beneficial. In FY2011 we also showed tissue specific differences in glucocorticoid receptor (GR) expression in immune cells, which correlated with presence of tissue damage in a mouse model of West Nile virus infection (Butts et al. 2011 Brain Beh Immun.) This suggests that GR expression may play a role in severity of local inflammation in the brain and its pathological sequelae. In our animal studies in GRdim glucocorticoid receptor (GR) impaired mice we have found that an intact GR is essential for full recovery from inflammatory challenge. These animal studies are currently being concluded to allow SNIB to fully focus on Project 1: clinical translational sweat patch studies.

项目 I。汗贴生物标志物：临床研究。这是SNIB目前的主要关注点。我们之前表明，在一组临床缓解的重度抑郁症 (MDD) 女性中，神经和免疫生物标志物可以在汗液中检测到，并且与血浆水平密切相关（Marques-Deak, 2006, J NutritionalMethods; Cizza 2008, Biol Psych）。具体而言，促炎细胞因子、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）均升高，而副交感神经肽血管活性肠多肽 (VIP) 显着降低。这种模式与 MDD 从副交感神经张力向交感神经张力的转变以及潜在的促炎症状态一致，这可能是导致对已知与 MDD 共病表达的疾病（包括心血管疾病、骨质疏松症和糖尿病）的易感性增强的原因。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特征在多大程度上反映特定疾病或健康状况，2011 财年，我们与其他 NIH 机构和校外机构合作，继续在五个正在进行的 IRB 批准的临床方案中应用汗贴，包括：(i) 埃默里大学 TRD-英夫利昔单抗研究。（埃默里大学 IRB 00011734，NIMH OHSR 豁免 #4025）； (ii) 巴西 - 强迫症研究（NIH 方案 IRB 3737）； (iii) 埃默里/CDC CFS 研究（埃默里大学 IRB 000551-2005，NIMH OHSR 豁免 #4026）； (iv) NCCAM - 太极拳/癌症幸存者研究（NCI 方案#06-AT-0016）； (v) GSA - 工作环境研究（NIA IRB 2003-142）。研究 (v)（GSA 工作场所研究）的结果表明，工作场所环境的物理特征与生理压力反应测量值的改变有关，与新办公空间中的受试者相比，旧办公空间中的受试者在醒来时唾液皮质醇的升高更大，心率变异性的昼夜节律变化更平坦（Thayer 等人，2010 Eur J Cardiovasc Prev Rehabil）。我们目前的研究重点是过渡到更高通量的静态抗体玻璃芯片微阵列平台，并利用纳米技术开发更好的贴片。 2010-11 财年，SNIB 与 NCCAM 主任合作，通过 NIH 主任挑战奖获得了对该项目的资金支持； NCCAM；神经科学和再生医学中心 (CNRM)/USUHS/DoD/NIH)；和 NIMH IRP 基金。项目 II 摘要：糖皮质激素抵抗、炎症和行为的动物模型：在我们评估类固醇激素孕酮对免疫细胞（树突状细胞，DC）功能、激活以及在炎症和宿主防御中的作用的影响的研究中，我们评估了来自淋巴（脾、骨髓、胸腺）和非淋巴（肝、肾、子宫）组织的 DC。我们的结果表明，非妊娠相关浓度的孕酮通过孕酮受体 (PR) 介导的机制抑制成熟 DC 产生促炎和辅助 T 细胞相关细胞因子、细胞表面标志物表达（共刺激分子和趋化因子受体）、细胞迁移/运动和 T 细胞增殖刺激，但对未成熟 DC 抗原摄取影响不大（Butts 等人，2009 年《分子生物学方法》；Butts 等人，2010 年《粘膜免疫》）。这些作用与糖皮质激素对 DC 功能的作用相当，表明孕酮在调节女性先天性和适应性免疫方面发挥着重要作用。我们还发现，黄体酮对 DC 功能的影响在整个啮齿动物动情周期中有所不同，并且取决于 PR 表达，而 PR 表达在体外和体内阴道内和腹膜内给药的整个周期中都有所变化。这表明女性的免疫反应在整个动情周期中发生生理变化，并且对于整个周期和怀孕期间对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影响情绪的细胞反应。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，因此黄体酮等改变细胞细胞因子产生的因素可能会导致女性在整个生命周期中不同的情绪障碍易感性。此外，黄体酮已被证明对创伤性脑损伤（TBI）和创伤后应激障碍（PTSD）具有有益的治疗作用。因此，这些数据对于了解黄体酮可能有益的发病机制和特定临床状况非常重要。在 2011 财年，我们还显示了免疫细胞中糖皮质激素受体 (GR) 表达的组织特异性差异，这与西尼罗河病毒感染小鼠模型中组织损伤的存在相关（Butts 等人，2011 Brain Beh Immun）。这表明 GR 表达可能在大脑局部炎症及其病理后遗症的严重程度中发挥作用。在我们对 GRdim 糖皮质激素受体 (GR) 受损的小鼠进行的动物研究中，我们发现完整的 GR 对于从炎症挑战中完全恢复至关重要。这些动物研究目前正在结束，以使 SNIB 能够完全专注于项目 1：临床转化汗斑研究。