Caspase-1 and Inflammasome Activation in Traumahemorrhagic Shock

创伤失血性休克中的 Caspase-1 和炎症小体激活

• 批准号: 8457529
• 负责人: Melanie J. Scott
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457529
• 关键词: Apoptosis; Apoptotic; Autophagocytosis; Caspase-1; Cell Death; Cell Survival; Cells; Cessation of life; Cleaved cell; Cysteine Protease; Data; Endothelial Cells; Epithelial Cells; Excision; Failure; Future; Goals; Hemorrhagic Shock; Hepatocyte; IL18 gene; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukins; Lead; Link; Liver; Measures; Mitochondria; Molecular; Multiple Organ Failure; Necrosis; Organ; Organ failure; Oxidative Stress; Pathway interactions; Patients; Prevention; Production; Proteins; Reactive Oxygen Species; Regulation; Research; Respiration; Role; Sepsis; Serum; Shock; Signal Pathway; Signal Transduction; Sirolimus; Starvation; Stimulus; Trauma; Up-Regulation; Vacuole; Work; base; cell type; cytokine; improved; injured; macrophage; monocyte; novel; novel therapeutics; prevent; public health relevance; response; therapeutic target

DESCRIPTION (provided by applicant): Controlling inflammation and cellular damage is the key to preventing and treating multiple organ failure (MOF) following trauma. However, many of the mechanisms that regulate inflammation and cell death in specific organs remain unknown. This means that despite advances in supportive measures for patients with MOF, there have been few advances in MOF treatments, or in our ability to adequately prevent the onset of MOF. Our overarching goal is to ultimately develop new therapeutics for trauma patients based on regulating the inflammatory response and its effects on cellular death and survival pathways following trauma and hemorrhagic shock (HS). In this proposal we will continue to investigate molecular pathways following HS that lead to activation of caspase-1 in end-organs, particularly liver. We will also determine how caspase-1 activation regulates autophagy and apoptosis, which in turn determines organ cell survival. Knowing how these cell-signaling pathways function and interact may help us to find future therapeutic targets for prevention and treatment of MOF after trauma. Our preliminary data suggest novel roles for caspase-1 in the liver during trauma/HS and during oxidative stresses. We have found that caspase-1 is a central regulator of autophagy in the liver following trauma/HS. Importantly, we have shown that caspase-1 activation is hepatoprotective after trauma/HS, in a manner independent of caspase-1-activated cytokines (IL1b/IL18) or a main inflammasome component, NLRP3. These findings challenge the paradigm that activation of caspase-1 by danger signals such as reactive oxygen species (ROS) occurs via the NLRP3-inflammasome. These preliminary findings lead us to our main hypothesis that caspase-1 activation occurs by cell-type specific mechanisms, and that caspase-1 function also differs in these cell types. We have shown that caspase-1 is central to the regulation of liver cell survival pathways during oxidative stress induced by HS. Without caspase-1, or where caspase-1 activation is inhibited, hepatocytes are less able to initiate cell survival strategies such as autophagy in response to HS. This results in increased apoptotic or necrotic cell death and increased levels of organ damage and failure. We expect to show that caspase-1 activation pathways differ after HS and are cell-type dependent. We also expect to show that caspase-1 has multiple novel functions in cells where production of IL1b/IL18 inflammatory cytokines is not the primary response to trauma. Understanding these novel pathways of inflammatory activation and function in individual cell types and organs may help us find new ways to treat and prevent MOF in trauma patients in the future.

描述（由申请人提供）：控制炎症和细胞损伤是预防和治疗创伤后多器官衰竭（MOF）的关键。然而，在特定器官中调节炎症和细胞死亡的许多机制仍然未知。这意味着，尽管对MOF患者的支持措施取得了进展，但在MOF治疗方面或我们充分预防MOF发作的能力方面几乎没有进展。我们的总体目标是最终开发新的治疗创伤患者的基础上调节炎症反应及其对细胞死亡和生存途径创伤和出血性休克（HS）的影响。在这个提议中，我们将继续研究HS后导致终末器官（特别是肝脏）中caspase-1激活的分子途径。我们还将确定caspase-1激活如何调节自噬和凋亡，这反过来又决定了器官细胞的存活。了解这些细胞信号通路的功能和相互作用可能有助于我们找到预防和治疗创伤后MOF的未来治疗靶点。我们的初步数据表明，在创伤/HS和氧化应激过程中，caspase-1在肝脏中的新作用。我们发现，caspase-1是创伤/HS后肝脏自噬的中心调节因子。重要的是，我们已经表明，caspase-1激活是肝保护创伤/HS后，在一种方式独立于caspase-1激活的细胞因子（IL 1b/IL 18）或主要的炎性体成分，NLRP 3。这些发现挑战了危险信号如活性氧（ROS）通过NLRP 3-炎性体激活caspase-1的范式。这些初步发现使我们的主要假设，caspase-1激活发生的细胞类型的具体机制，caspase-1的功能也不同，在这些细胞类型。我们已经表明，半胱天冬酶-1是中央的氧化应激诱导的HS过程中的肝细胞存活途径的调节。没有半胱天冬酶-1，或半胱天冬酶-1激活被抑制，肝细胞不太能够启动细胞存活策略，如自噬响应HS。这导致细胞凋亡或坏死性细胞死亡增加以及器官损伤和衰竭水平增加。我们希望表明，半胱天冬酶-1激活途径不同后HS和细胞类型依赖性。我们还期望表明，caspase-1在细胞中具有多种新功能，其中IL 1b/IL 18炎性细胞因子的产生不是对创伤的主要反应。了解这些新的炎症激活途径和功能在个别细胞类型和器官可能有助于我们找到新的方法来治疗和预防多器官功能衰竭的创伤患者在未来。