Characterization of Burn-Induced Hepatic Apoptosis

烧伤诱导的肝细胞凋亡的特征

• 批准号: 8320003
• 负责人: Marc Gerhard Jeschke
• 金额: $ 19.92万
• 依托单位: SUNNYBROOK & WOMEN'S COLL HLTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320003
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; Acute-Phase Reaction; Apoptosis; Apoptotic; Attenuated; Basic Science; Burn Trauma; Burn injury; Ca(2+)-Transporting ATPase; Calcium; Calcium-Binding Proteins; Cell Death; Chemicals; Clinical; Data; Functional disorder; Glucose; Hepatic; Hepatocyte; ITPR1 gene; Infection; Inflammation; Inflammatory; Injury; Inositol; Insulin; Insulin Receptor; Intervention; Knowledge; Lead; Link; Liver; Mediating; Metabolic; Metabolic Pathway; Metformin; Mitochondria; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Outcome; PAWR protein; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Physiological; Play; Process; Proteins; Rattus; Recovery; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stress; Structure; Surgeon; Testing; Therapeutic Intervention; adverse outcome; attenuation; base; clinical care; cytochrome c; design; endoplasmic reticulum stress; experience; heat injury; immune function; improved; in vivo; inhibitor/antagonist; innovation; liver function; mitochondrial dysfunction; mortality; novel; novel therapeutics; public health relevance; receptor; receptor coupling; response; tripolyphosphate

DESCRIPTION (provided by applicant): The role of the liver during the post-burn response is essentially unknown, and many burn and trauma surgeons consider the liver as unimportant, with little or no effect on post-burn outcomes. Others strongly suggest that intact liver function and integrity are essential for burn patients' recovery, because the liver modulates metabolic pathways, inflammatory processes, immune functions, and acute-phase responses. Our preliminary data indicate that a severe thermal injury causes hepatic damage and dysfunction by inducing hepatocyte endoplasmic reticulum stress (ER stress) and hepatocyte apoptosis. We hypothesize that hepatic ER stress and subsequent apoptosis contribute to adverse post-burn outcomes, and that attenuating hepatic ER stress and apoptosis will enhance hepatic function, which is associated with improved post-burn morbidity and mortality. The exact mechanisms by which a burn induces hepatic ER stress, apoptosis, and dysfunction are not known, limiting therapeutic intervention. In preliminary studies we found that these pathophysiological processes are related to hepatic inflammation, altered phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, depletion of the hepatic calcium stores, the unfolded protein response (UPR), and mitochondrial dysfunction. We now propose to characterize the post-burn molecular and physiological changes that lead to hepatic apoptosis and dysfunction. Hypothesis 2 is that burn induces hepatic damage by altering the PI3K/Akt and inositol 1, 4, 5,-triphosphate receptor (IP3R) signaling pathways, leading to calcium store depletion, cytochrome c release, ER stress/UPR, and consequently to hepatocyte apoptosis. In Aim 1 we will determine whether post-burn hepatocyte ER stress and apoptosis contribute to morbidity and mortality. Aim 2 is to determine in vivo the cellular and sub-cellular mechanisms which cause post-burn alterations in hepatic intracellular calcium, ER stress and UPR, and hepatocyte apoptosis. Aim 3 is designed to identify and characterize an intervention that will improve hepatic integrity and function post-burn and is readily available in the clinical setting. Based on our preliminary data we will use insulin, which attenuates hepatic damage and improves liver function post-burn. The mechanisms underlying these effects are not understood; we hypothesize that post-burn insulin administration improves hepatocyte viability and liver function via normalization of intracellular calcium and IP3R signaling pathways, attenuation of cytochrome c release, and reduction of ER stress/UPR, leading to markedly decreased hepatocyte apoptosis. We further hypothesize that insulin exerts its effects via insulin-specific signal transduction pathway activation. We will test this hypothesis by comparing the effects of insulin on hepatocyte ER stress/UPR and apoptosis to the effects of a glucose- lowering drug, as well as chemical ER chaperones on ER stress/UPR, apoptosis, and post-burn outcomes. Identifying and understanding the cellular and molecular mechanisms by which insulin or glucose modulation will improve outcomes could lead to the establishment of novel treatment options for severely burned patients. PUBLIC HEALTH RELEVANCE: A key and novel aspect of this study is our hypothesis that hepatic apoptosis and ER stress play an important role in post-burn morbidity and mortality, and that insulin administration improves these adverse outcomes by decreasing hepatic apoptosis and ER stress. This study is important because characterizing and identifying the molecular mechanisms associated with burn-induced hepatic apoptosis and ER stress will lead to improvements in the clinical care of severely burned patients.

描述（由申请人提供）：肝脏在烧伤后反应中的作用基本上是未知的，许多烧伤和创伤外科医生认为肝脏不重要，对烧伤后结局影响很小或没有影响。其他人强烈认为，完整的肝功能和完整性对烧伤患者的康复至关重要，因为肝脏调节代谢途径、炎症过程、免疫功能和急性期反应。我们的初步数据表明，严重的热损伤通过诱导肝细胞内质网应激（ER应激）和肝细胞凋亡引起肝损伤和功能障碍。我们假设肝脏ER应激和随后的细胞凋亡有助于烧伤后的不良结局，并且减弱肝脏ER应激和细胞凋亡将增强肝功能，这与改善烧伤后的发病率和死亡率相关。烧伤诱导肝ER应激、细胞凋亡和功能障碍的确切机制尚不清楚，限制了治疗干预。在初步研究中，我们发现这些病理生理过程与肝脏炎症、改变的磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（Akt）信号传导、肝脏钙储备耗竭、未折叠蛋白反应（UPR）和线粒体功能障碍有关。我们现在提出的特点烧伤后的分子和生理变化，导致肝细胞凋亡和功能障碍。假设2是烧伤通过改变PI 3 K/Akt和肌醇1，4，5-三磷酸受体（IP 3R）信号通路诱导肝损伤，导致钙库耗竭、细胞色素c释放、ER应激/UPR，并因此导致肝细胞凋亡。在目标1中，我们将确定烧伤后肝细胞内质网应激和细胞凋亡是否有助于发病率和死亡率。目的二是探讨烧伤后肝细胞内钙离子、内质网应激和UPR变化及肝细胞凋亡的细胞和亚细胞机制。目的3旨在确定和表征一种干预措施，该措施将改善烧伤后的肝脏完整性和功能，并且在临床环境中易于获得。根据我们的初步数据，我们将使用胰岛素，它可以减轻肝损伤，改善烧伤后的肝功能。这些影响的机制尚不清楚;我们假设烧伤后胰岛素给药通过细胞内钙和IP 3R信号通路的正常化，细胞色素c释放的衰减和ER应激/UPR的减少来改善肝细胞活力和肝功能，导致肝细胞凋亡显著减少。我们进一步假设胰岛素通过胰岛素特异性信号转导途径激活发挥其作用。我们将通过比较胰岛素对肝细胞ER应激/UPR和细胞凋亡的影响与降糖药物以及化学ER分子伴侣对ER应激/UPR、细胞凋亡和烧伤后结果的影响来验证这一假设。识别和理解胰岛素或葡萄糖调节将改善结果的细胞和分子机制可能导致为严重烧伤患者建立新的治疗方案。 公共卫生关系：这项研究的一个关键和新颖的方面是我们的假设，肝细胞凋亡和ER应激在烧伤后发病率和死亡率中起重要作用，胰岛素给药通过减少肝细胞凋亡和ER应激改善这些不良结局。这项研究是重要的，因为表征和识别与烧伤诱导的肝细胞凋亡和ER应激相关的分子机制将导致严重烧伤患者的临床护理的改善。