Neuroendocrine Stress Response in Inflammatory & Behavio

炎症的神经内分泌应激反应

• 批准号: 7136243
• 负责人: ESTHER M. STERNBERG
• 金额: --
• 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/7136243
• 关键词: anthrax toxin; behavioral genetics; chromatin immunoprecipitation; corticosteroid receptors; corticotropin releasing factor; cytokine; gel mobility shift assay; genetic polymorphism; genetic susceptibility; human tissue; hypothalamic pituitary adrenal axis; hypothalamus; inflammation; laboratory mouse; laboratory rat; linkage mapping; lipopolysaccharides; neuroendocrine system; neuroimmunomodulation; nuclear receptors; progesterone receptors; psychoneuroimmunology; septic shock; stress

The research of the Section on Neuroendocrine Immunology and Behavior (SNIB) focuses on (Project 1) molecular basis of differential hypothalamic pituitary adrenal (HPA) axis regulation in inbred rat strains and its relationship to inflammatory disease susceptibility and (Project 2) repression of the glucocorticoid receptor and other nuclear hormone receptors by Bacillus anthracis (anthrax) lethal toxin (LeTx) and its role in inflammatory shock. In Project 1, we have begun to explore the expression within the brain of immune molecules (cytokines and chemokines) in rodents exposed to bacterial cell wall products. Preliminary results indicate that certain immune molecules (chemokines) are expressed within the brain under these conditions. Project 2 focuses on validation and elucidation of the molecular mechanisms and therapeutic implications of our 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. We 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. Since GR antagonists or interruptions of the hypothalamic-pituitary-adrenal (HPA) axis render otherwise shock-resistant animals highly susceptible to the lethal effects of many bacterial products, we postulated that LeTx repression of GR and other nuclear hormone receptors might contribute to anthrax toxicity and lethality. In subsequent studies we have shown that interruption of the HPA axis by adrenalectomy is associated with enhanced LeTx mortality in otherwise LeTx resistant mouse strains. Furthermore, treatment of mice with glucorticoids was associated with enhanced mortality. Follow-up molecular studies show selective repression of nuclear hormone receptors that is partially receptor and partially promoter dependent. Chromatin immunoprecipitation (ChIP) experiments indicate that LeTx inhibits GR binding to the promoter, resulting in loss of both polymerase II binding and acetylation of histone H3 in target genes. Electrophoretic mobility shift assays (EMSA) indicate that this inhibition is not due to direct interaction of LF ? PA with the GR-GRE complex. Taken together, these findings indicate that LeTx represses GR activity through its effects on co-factor(s), or modification of the receptor. These findings together with the in vivo studies indicate that an intact HPA axis (neuroendocrine response) is required for resistance to anthrax lethal toxin, and that simple glucocorticoid replacement may not be sufficient and might be detrimental as a therapy for anthrax LeTx shock.

神经内分泌、免疫学和行为学科的研究重点是：（项目1）近交系大鼠下丘脑-垂体-肾上腺（HPA）轴不同调节的分子基础及其与炎症性疾病易感性的关系;（项目2）炭疽杆菌致死毒素（LeTx）对糖皮质激素受体和其他核激素受体的抑制及其在炎症性休克中的作用。 在项目1中，我们已经开始探索暴露于细菌细胞壁产物的啮齿动物脑内免疫分子（细胞因子和趋化因子）的表达。初步结果表明，某些免疫分子（趋化因子）在这些条件下在脑内表达。 项目2的重点是验证和阐明的分子机制和我们的发现，炭疽杆菌致死毒素（LeTx）是一种有效的和选择性的核激素受体，包括糖皮质激素受体（GR）和孕酮受体（PR）的阻遏物的治疗意义。这些发现对治疗和预防炭疽LeTx和其他细菌毒素有重要意义？毒性和致命性。我们对初步研究进行了随访，这些研究表明纳摩尔浓度的LeTx选择性抑制核激素受体活性，包括糖皮质激素受体（GR），孕酮受体（PR）和雌激素受体（ER）α，但不抑制盐皮质激素受体（MR）或ER β。由于GR拮抗剂或中断的下丘脑-垂体-肾上腺（HPA）轴，否则休克抵抗动物非常容易受到许多细菌产品的致死作用，我们推测，LeTx抑制GR和其他核激素受体可能有助于炭疽毒性和致死性。在随后的研究中，我们已经表明，通过肾上腺切除术中断HPA轴与增强的LeTx死亡率相关，否则LeTx耐药小鼠品系。此外，用糖皮质激素治疗小鼠与死亡率增加相关。后续的分子研究表明，选择性抑制核激素受体，这是部分受体和部分启动子依赖性。染色质免疫沉淀（ChIP）实验表明，LeTx抑制GR与启动子的结合，导致靶基因中聚合酶II结合和组蛋白H3乙酰化的损失。电泳迁移率变动分析（EMSA）表明，这种抑制是由于LF？PA与GR-GRE复合体。总之，这些发现表明LeTx通过其对辅因子的影响或受体的修饰来抑制GR活性。这些发现与体内研究一起表明，完整的HPA轴（神经内分泌反应）是抵抗炭疽致死毒素所必需的，并且简单的糖皮质激素替代可能是不够的，并且作为炭疽LeTx休克的治疗可能是有害的。