Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

项目一：汗液贴片生物标志物：临床研究。我们之前的研究表明，在一组临床缓解的重度抑郁症（MDD）女性患者中，汗液中可检测到神经和免疫生物标志物，并与血浆水平密切相关（Marques-Deak, 2006, J Immunol Methods; Cizza 2008, Biol Psych）。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）和降钙素基因相关肽CGRP（降钙素基因相关肽）升高，副交感神经肽血管活性肠多肽（VIP）显著降低。这种模式与MDD从副交感神经向交感神经的转变是一致的，并且潜在的促炎状态可以解释对已知与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在多大程度上反映特定疾病或健康状况，在2010财年，我们正在与其他NIH研究所和校外机构合作，在五个正在进行的IRB批准的临床方案中应用汗液贴生物标志物，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）；巴西-强迫症研究（NIH方案IRB 3737）；（iii） Emory/CDC CFS研究（Emory University IRB 000551-2005， NIMH OHSR豁免#4026）；（iv） NCCAM -太极拳/癌症幸存者研究（NCI协议#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改变有关，这表明，与新办公场所相比，在旧办公场所办公的受试者在醒来时唾液皮质醇的上升幅度更大，心率变异性的昼夜节律变化更平缓（Thayer等人，2010年Eur J cardiovascular Prev Rehabil）。

PROJECT I. Sweat Patch Biomarkers: Clinical Studies. 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 FY10 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). 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). 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 (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 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 FY2010 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 viral infection (Butts et al. in press 2010 Brain Beh Immun.) This suggests that GR expression may play a role in severity of local inflammation and its pathological sequelae.