Cholinergic regulation of NF-kB in sepsis

脓毒症中 NF-kB 的胆碱能调节

基本信息

批准号：
7668512
负责人：
Luis Ulloa
金额：
$ 29.64万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-05 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7668512
关键词：
Accounting Acetylcholine Acute Affect Agonist Anti-Inflammatory Agents Anti-inflammatory Antibiotics Apoptosis Attenuated Cause of Death Cell Line Cells Cessation of life Cholinergic Agonists Clinical Treatment Clinical Trials Coronary Critical Care Disease Endotoxemia Goals Hemorrhage Immune Infection Inflammation Inflammatory Inflammatory Response Intensive Care Knockout Mice Ligation MAP Kinase Gene Mediating Molecular Multiple Organ Failure Mus Myocardial NF-kappa B Nicotine Nicotinic Agonists Nicotinic Receptors Onset of illness Organ Pathway interactions Patients Physiological Processes Process Production Puncture procedure Regulation STAT3 gene Sepsis Shock Societies Spleen Therapeutic Time Toxic effect Trauma Ulcerative Colitis United States alpha-bungarotoxin receptor cholinergic cytokine design human morbidity improved in vivo macrophage mortality novel novel therapeutics prevent public health relevance receptor

项目摘要

DESCRIPTION (provided by applicant): Currently, there is no effective, safe clinical treatment for sepsis, which accounts for 9.3% of the overall deaths in the United States annually. Sepsis is not only related to infections. Shock, trauma, hemorrhage, and other conditions of critical care contribute to severe sepsis, which is characterized by an overwhelming systemic inflammatory response that causes lethal multiple organ failure. Our goal is to develop novel therapeutic strategies to restrain systemic inflammation and improve survival in experimental sepsis. Treatment with cholinergic agonists such as nicotine, started one day after the onset of the disease, also attenuate systemic inflammation and "rescue" mice from "established" sepsis both in lethal endotoxemia and cecal ligation and puncture. Nicotine has been already used in clinical trials for inflammatory disorders such as ulcerative colitis, but the therapeutic potential of this mechanism is underestimated due to the collateral toxicity of nicotine. There are two fundamental considerations limiting the translational potential of this mechanism in critical care: (1) identification of the specific receptor(s) involved in the process; and (2) identification of the mechanism inhibiting the production of cytokines and pathological markers associated with sepsis. Our studies in RAW264.7 macrophage-like cells indicate that cholinergic agonists inhibit the production of proinflammartory cytokines by modulating NF-kB through a mechanism dependent on the alpha7 nicotinic acethlcholine receptor (nAChR). Since our most recent studies indicate that nicotine attenuates systemic inflammation and improves survival in sham but not in splenectomized mice, we propose to study the implications of these two factors in the spleen. Our objectives are to determine whether cholinergic agonists inhibit a specific step of the NF-kB pathway in the spleen and whether cholinergic agonists modulate NF-kB in the spleen through a mechanism mediated by the alpha7nAChR. If so, specific alpha7nAChR-agonists may represent a promising pharmacological strategy to avoid the toxicity of nicotine and modulate NF-kB in specific immune cells during infectious and inflammatory disorders. PUBLIC HEALTH RELEVANCE Currently, there is no effective, safe clinical treatment for sepsis, which accounts for 9.3% of the overall deaths in the United States annually. Our goal is to determine the molecular mechanism by which cholinergic agonists restrain systemic inflammation in sepsis. These studies will allow the design of novel pharmacological strategies to improve survival in sepsis

描述（由申请人提供）：目前，脓毒症尚无有效、安全的临床治疗方法，脓毒症每年占美国总死亡人数的 9.3%。败血症不仅与感染有关。休克、创伤、出血和其他重症监护条件会导致严重脓毒症，其特点是压倒性的全身炎症反应，导致致命的多器官衰竭。我们的目标是开发新的治疗策略来抑制全身炎症并提高实验性脓毒症的生存率。在疾病发作一天后开始使用尼古丁等胆碱能激动剂进行治疗，也可以减轻全身炎症，并在致命性内毒素血症和盲肠结扎和穿刺中“拯救”小鼠免于“既定”败血症。尼古丁已被用于治疗溃疡性结肠炎等炎症性疾病的临床试验，但由于尼古丁的附带毒性，这种机制的治疗潜力被低估。有两个基本考虑因素限制了该机制在重症监护中的转化潜力：（1）识别该过程中涉及的特定受体； (2)鉴定抑制与脓毒症相关的细胞因子和病理标志物产生的机制。我们对 RAW264.7 巨噬细胞样细胞的研究表明，胆碱能激动剂通过依赖于 α7 烟碱乙酰胆碱受体 (nAChR) 的机制调节 NF-kB，从而抑制促炎细胞因子的产生。由于我们最近的研究表明尼古丁可以减轻假手术小鼠的全身炎症并提高存活率，但不能提高脾切除小鼠的存活率，因此我们建议研究这两个因素对脾脏的影响。我们的目标是确定胆碱能激动剂是否抑制脾脏中 NF-kB 通路的特定步骤，以及胆碱能激动剂是否通过 α7nAChR 介导的机制调节脾脏中的 NF-kB。如果是这样，特定的 α7nAChR 激动剂可能代表一种有前途的药理学策略，可以避免尼古丁的毒性并在感染性和炎症性疾病期间调节特定免疫细胞中的 NF-kB。公共卫生相关性目前，脓毒症尚无有效、安全的临床治疗方法，脓毒症每年占美国总死亡人数的 9.3%。我们的目标是确定胆碱能激动剂抑制脓毒症全身炎症的分子机制。这些研究将有助于设计新的药理学策略来提高脓毒症患者的生存率