Endogenous regulators of inflammation in liver ischemia/reperfusion

肝脏缺血/再灌注炎症的内源性调节因子

• 批准号: 8331458
• 负责人: Allan Tsung
• 金额: $ 28.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331458
• 关键词: Acetylation; Acute; Calcium/calmodulin-dependent protein kinase; Cell Nucleus; Cells; Cerebral Ischemia; Clinical; DNA; Dendritic Cells; Disease; Distal; Eukaryotic Cell; Event; Extracellular Space; Family; Functional disorder; HMGB1 Protein; Hepatic; Hepatocellular Damage; Hepatocyte; Histone Deacetylase; Hypovolemic Shock; Immune; Immune response; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Invaded; Ischemia; Link; Liver; Mediating; Mediator of activation protein; Modeling; Modification; Molecular; Morbidity - disease rate; Myocardial Infarction; Natural Immunity; Nuclear; Nuclear Protein; Nucleosomes; Operative Surgical Procedures; Organ; Organ Transplantation; Oxidative Stress; Pathway interactions; Pattern; Pattern recognition receptor; Play; Process; Production; Property; Proteins; Reperfusion Injury; Reperfusion Therapy; Role; Sepsis; Signal Pathway; Solid; Stress; Surface; TLR4 gene; Testing; Time; Tissues; Toll-like receptors; Trauma; Work; antimicrobial; base; calmodulin-dependent protein kinase II; cell type; clinically relevant; design; improved; in vivo; liver function; liver ischemia; macrophage; microbial; mortality; novel; pathogen; prevent; research study; response; transcription factor

DESCRIPTION (provided by applicant): Thorough understanding of the pathophysiology of liver ischemia reperfusion (I/R) is vital as it is commonly encountered clinically during elective liver surgical procedures, solid organ transplantation, trauma, and hypovolemic shock. Although the distal events involved in the inflammatory response resulting in liver damage after I/R injury has been well-studied, the proximal events dictating the propagation of the inflammatory response and further tissue damage is poorly understood. This proposal will study the mechanisms by which high mobility group box 1 (HMGB1), a nuclear protein involved in regulating interactions between DNA and transcription factors, can act as a key alarm molecule when released extracellularly during ischemic stress to active inflammatory responses. We propose that during ischemic stress, the parenchymal cells of the liver (hepatocyte), initially mobilize and release nuclear HMGB1. HMGB1 is then sensed by pattern recognition receptors, such as the family of toll-like receptors (TLR), expressed on neighboring immune cells to provide a critical link between tissue damage and activation and recruitment of the innate immune response. In Aim 1, we will determine the signaling pathways governing the active release of HMGB1 from hepatocytes following oxidative stress. We will demonstrate the mechanisms by which calcium/ calmodulin-dependent protein kinase II control the acetylation status and subsequent release of HMGB1 through modification of histone deacetylase activity. In Aim 2, we will show the key roles TLR4 play in HMGB1-mediated inflammation in vivo using a model of liver I/R. In Aim 3, we will focus on hepatic dendritic cells as the primary immune cell type that responds to HMGB1 and regulates the inflammatory response to ischemic injury. These studies will serve as a basis for developing both a more comprehensive understanding of how innate immune cells are activated during liver I/R, and should prove useful in the design of novel therapies to minimize liver damage in a variety of surgical settings. Importantly, the mechanisms of inflammation mediated by HMGB1 release is likely common in a number of infectious and non-infectious inflammatory conditions found within the liver and the implications of this work likely extend to a variety of other ischemic conditions (e.g. myocardial infarction and cerebral ischemia).

描述（由申请人提供）：对肝缺血再灌注（I/R）的病理生理学的透彻理解至关重要，因为在选修肝外科手术程序，固体器官移植，创伤和低血压冲击过程中通常会在临床上遇到临床。尽管对炎症反应涉及的远端事件进行了充分研究，导致I/R损伤后肝脏损伤，但近端事件决定了炎症反应的传播和进一步的组织损伤的传播。该提案将研究高迁移率组框1（HMGB1）（一种参与调节DNA和转录因子之间相互作用的核蛋白）的机制，当在缺血性压力对主动炎症反应期间细胞外释放时，可以作为关键警报分子。我们建议在缺血性压力，肝脏的实质细胞（肝细胞），最初动员并释放核HMGB1。然后，通过模式识别受体（例如Toll样受体（TLR）家族）在邻近的免疫细胞上表达的HMGB1感测，以提供组织损伤与激活与先天免疫反应的募集之间的关键联系。在AIM 1中，我们将确定控制HMGB1在氧化应激之后从肝细胞中主动释放的信号通路。我们将证明钙/钙调蛋白依赖性蛋白激酶II通过修饰组蛋白脱乙酰基酶活性来控制乙酰化状态和随后释放HMGB1的机制。在AIM 2中，我们将使用肝I/R模型在体内显示HMGB1介导的炎症中TLR4的关键作用。在AIM 3中，我们将专注于肝树突状细胞作为对HMGB1反应并调节缺血性损伤的炎症反应的主要免疫细胞类型。这些研究将成为对肝I/R期间先天免疫细胞如何激活的更全面了解的基础，并且应该证明在设计新型疗法方面有用，以最大程度地减少各种外科手术环境中的肝脏损伤。重要的是，HMGB1释放介导的炎症机制可能在肝内发现的许多传染性和非感染性炎症条件下很常见，这项工作的含义可能扩展到其他多种脑部缺血状况（例如，心肌梗死和脑局部缺血）。