Role of Neuroendocrine Stress Response in Inflammatory a

神经内分泌免疫和行为(SNIB)部分的研究已转移到我们发现炭疽杆菌(炭疽杆菌)、致命毒素(LeTx)和其他细菌毒素对糖皮质激素受体和其他核激素受体的抑制以及这种作用在炎症性休克中的作用(项目1)。此外，我们正在研究孕酮对先天炎症细胞反应的影响，特别是树突状细胞(项目2)。在一项临床研究(项目3)中，我们已经验证了一种测量汗液中细胞因子的方法，目前正在将这种验证扩展到其他临床研究。 在项目1中，我们正在扩大我们的研究，基于我们的初步发现，炭疽杆菌致命毒素(LeTx)是包括糖皮质激素受体(GR)和孕激素受体(PR)在内的核激素受体的有效和选择性抑制物。这些发现对炭疽、LeTx和其他细菌毒素的治疗和预防具有重要意义。毒性和致命性。我们目前的研究集中在(A)阐明这种效应的分子机制；(B)确定这种效应是否延伸到其他细菌毒素；(C)确定这种体外效应的体内相关性；以及(D)治疗意义。我们首先跟进了最初的研究，发现纳摩尔浓度的LeTx选择性地抑制核激素受体的活性，包括糖皮质激素受体(GR)、孕激素受体(PR)和雌激素受体(ER)α，但不包括盐皮质激素受体(MR)或ERβ。分子研究表明，这种效应既依赖于受体，也依赖于启动子，复合启动子(MMTV)对许多核激素受体的影响比单一的GRE启动子更大。目前的研究正在进行中，使用复杂启动子的突变结构来确定这些毒素所需的启动子区域的准确位置？压抑效应。在其他研究中，我们已经确定这种核激素受体抑制作用延伸到其他细菌毒素，包括索氏梭菌致死毒素和艰难梭菌毒素A和B。目前的研究旨在确定这些体外效应是否与这些毒素的体内效应有关，以及在体外和体内系统测试潜在的治疗药物。 在项目2中，我们发现孕酮通过受体介导的机制抑制成熟树突状细胞的激活，包括促炎细胞因子的产生和共刺激分子的表达，但对未成熟树突状细胞没有影响。 在项目3中，我们验证了一种测量汗液中免疫和应激生物标志物的方法，使用皮肤贴片，并使用循环免疫亲和层析和质谱仪对样品进行分析。目前的研究集中于将这些研究扩展到包括更多的受试者和不同条件下的受试者。

The research of the Section on Neuroendocrine Immunology and Behavior (SNIB) has shifted to focus primarily on our discovery of the repression of the glucocorticoid receptor and other nuclear hormone receptors by Bacillus anthracis (anthrax) lethal toxin (LeTx) and other bacterial toxins and the role of this effect in inflammatory shock (Project 1). In addition we are studying the effects of progesterone on innate inflammatory cell responses, specifically dendritic cells (Project 2). In a clinical study (Project 3) we have validated a method to measure cytokines in sweat and are currently extending this validation to other clinical studies. In Project 1, we are extending our research based on our initial finding that Bacillus anthracis lethal toxin (LeTx) is a potent and selective repressor of nuclear hormone receptors, including the glucocorticoid receptor (GR) and progesterone receptor (PR). These findings have important implications for treatment and prevention of anthrax LeTx and other bacterial toxins? toxicity and lethality. Our current studies focus on (a) elucidation of the molecular mechanisms of this effect; (b) determination of whether this effect extends to other bacterial toxins; (c) determination of the in vivo correlates of this in vitro effect; and (d) therapeutic implications. We first followed up on initial studies showing that nanomolar concentrations of LeTx selectively repress nuclear hormone receptor activity, including the glucocorticoid receptor (GR), the progesterone receptor (PR) and the estrogen receptor (ER) alpha but not the mineralocorticoid receptor (MR) or ER beta. Molecular studies indicate that this effect is both receptor and promoter dependent, with complex promoters (MMTV) showing greater effects on many nuclear hormone receptors than the simple GRE promoter. Current studies are in progress using mutant constructs of complex promoters to identify the precise location in the promoter region that is required for these toxins? repressive effects. In other studies we have determined that this nuclear hormone receptor repressive effect extends to other bacterial toxins, including C. sordellii lethal toxin and C. difficile Toxins A and B. Current studies are aimed at determining whether these in vitro effects are relevant to in vivo effects of these toxins, as well as testing potential therapeutic agents in both in vitro and in vivo systems. In Project 2 we have found that progesterone, through a receptor-mediated mechanism, suppresses mature dendritic cell activation, including production of pro-inflammatory cytokines and co-stimulatory molecule expression, but has no effect on immature dendritic cells. In Project 3 we have validated a method for measuring immune and stress biomarkers in sweat, using skin patches and assay of samples using recycling immunoaffinity chromoatography and mass spectrometry. Current studies focus on extending these studies to include larger numbers of subjects and subjects under different conditions.