Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

项目I：汗斑生物标记物：临床研究。这是目前Snib的主要关注点。我们以前发现，神经和免疫生物标记物可以在汗液中检测到，并与临床缓解期的一组患有严重抑郁障碍(MDD)的女性的血浆水平密切相关(Marque-Deak，2006，J免疫学方法；Cizza 2008，生物精神病学)。尤其是促炎细胞因子升高，交感神经肽Y(NPY)和感觉/疼痛相关神经肽P物质(SP)和降钙素基因相关肽(CGRP)升高，而副交感神经肽血管活性肠肽(VIP)显著降低。这一模式与MDD从副交感音调向交感音调的转变以及潜在的促炎状态一致，这可能是MDD对已知与MDD共同表达的疾病的易感性增加的原因，包括心血管疾病、骨质疏松症和糖尿病。此外，生物标记物水平与抑郁和焦虑症状密切相关，表明这些生物标记物的功能意义。为了确定特定生物标记物特征反映特定疾病或健康状况的程度，在2011财年，我们与其他NIH研究所和校外机构合作，继续在IRB批准的五个正在进行的临床方案中应用汗片，包括：(I)埃默里大学TRD-Infliximab研究。(Ii)巴西--强迫症研究(NIH IRB 3737号议定书)；(3)Emory/CDC CFS研究(Emory University IRB 000551-2005年，NIMH OHSR豁免#4026)；(Iv)NCCAM--太极/癌症幸存者研究(NCI#06-AT-0016)；(V)GSA--工作环境研究(NIA IRB 2003-142)。研究(V)的结果(GSA工作场所研究)表明，工作场所环境的物理特征与生理应激反应的测量变化有关，这表明，与新办公室相比，占据旧办公室空间的受试者在醒来时唾液皮质醇的上升更大，心率变异性的昼夜变化更平缓(塞耶等人)。2010欧元J心脏康复)。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补丁。在2010-2011财年，SNIB通过与NCCAM主任、NCCAM主任、神经科学和再生医学中心(CNRM/USUHS/DoD/NIH)和NIMH IRP基金合作，获得了对该项目的资金支持。 项目II概述：糖皮质激素抵抗、炎症和行为的动物模型：在我们的研究中，我们评估了类固醇激素孕酮对免疫细胞(DC)功能、激活的影响，以及在炎症和宿主防御中的作用，我们评估了来自淋巴组织(脾、骨髓、胸腺)和非淋巴组织(肝、肾、子宫)的DC。我们的结果表明，孕酮在非妊娠相关浓度下，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、细胞表面标记表达(共刺激分子和趋化因子受体)、细胞迁移/运动和刺激T细胞增殖，但对未成熟DC抗原摄取几乎没有影响(Butts等人)。2009方法：Mol Biol；Butts et al.2010粘膜免疫)。这些效应可与糖皮质激素对DC功能的影响相媲美，表明孕酮在调节女性的先天免疫和获得性免疫中起重要作用。我们还发现，孕酮对DC功能的影响在整个啮齿动物发情周期中都是不同的，并且依赖于PR的表达，在体外和体内，通过阴道和腹腔给药，PR的表达都会发生变化。这表明，在整个发情周期中，女性的免疫反应在生理上是不同的，并对整个发情周期和怀孕期间的感染和炎症的临床易感性具有重要的意义。荷尔蒙状态的这种生理波动也可能影响对情绪起作用的细胞反应。由于已知细胞因子可以影响情绪，并可能在某些形式的抑郁症以及疾病行为中的情绪变化中发挥作用，孕酮等因素可以改变细胞产生的细胞因子，从而导致女性在整个生命周期中对情绪障碍的不同易感性。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)有有益的治疗效果。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的临床条件很重要。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有关(Butts等人。2011 Brain Beh Immun。)提示GR的表达可能在脑局部炎症的严重程度及其病理后遗症中起一定作用。在我们对糖皮质激素受体(GR)受损小鼠的动物研究中，我们发现完整的GR对于炎症攻击的完全恢复是必不可少的。这些动物研究目前正在完成，以使Snib能够完全专注于项目1：临床转化性汗斑研究。

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.