Characterization of Burn-Induced Hepatic Apoptosis

烧伤诱导的肝细胞凋亡的特征

• 批准号: 8538339
• 负责人: Marc Gerhard Jeschke
• 金额: $ 19.04万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538339
• 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; 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; liver injury; 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，对烧伤后的结果影响很小或没有影响。其他人强烈建议完整的肝功能和完整性对​​于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）和肝细胞凋亡而导致肝损伤和功能障碍。我们假设肝脏 ER 应激和随后的细胞凋亡会导致不良的烧伤后结局，并且减弱肝脏 ER 应激和细胞凋亡将增强肝功能，这与改善烧伤后发病率和死亡率相关。烧伤引起肝脏内质网应激、细胞凋亡和功能障碍的确切机制尚不清楚，这限制了治疗干预。在初步研究中，我们发现这些病理生理过程与肝脏炎症、磷酸肌醇 3 激酶 (PI3K)/蛋白激酶 B (Akt) 信号传导改变、肝钙储存消耗、未折叠蛋白反应 (UPR) 和线粒体功能障碍有关。我们现在建议描述导致肝细胞凋亡和功能障碍的烧伤后分子和生理变化。假设 2 认为烧伤通过改变 PI3K/Akt 和肌醇 1,4,5,-三磷酸受体 (IP3R) 信号通路诱导肝损伤，导致钙储备耗尽、细胞色素 C 释放、内质网应激/UPR，从而导致肝细胞凋亡。在目标 1 中，我们将确定烧伤后肝细胞 ER 应激和细胞凋亡是否会导致发病率和死亡率。目标 2 是确定体内引起烧伤后肝细胞内钙、内质网应激和 UPR 以及肝细胞凋亡变化的细胞和亚细胞机制。目标 3 旨在确定和描述一种干预措施，该干预措施将改善烧伤后的肝脏完整性和功能，并且易于在临床环境中使用。根据我们的初步数据，我们将使用胰岛素，它可以减轻肝损伤并改善烧伤后的肝功能。这些影响背后的机制尚不清楚；我们假设烧伤后注射胰岛素可通过细胞内钙和 IP3R 信号通路正常化、细胞色素 C 释放减弱以及 ER 应激/UPR 减少来改善肝细胞活力和肝功能，从而显着减少肝细胞凋亡。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 伴侣对 ER 应激/UPR、细胞凋亡和烧伤后结果的影响来检验这一假设。识别和理解胰岛素或葡萄糖调节改善预后的细胞和分子机制可能会为严重烧伤患者建立新的治疗方案。 公共健康相关性：本研究的一个关键且新颖的方面是我们的假设，即肝细胞凋亡和 ER 应激在烧伤后发病率和死亡率中发挥重要作用，并且胰岛素给药通过减少肝细胞凋亡和 ER 应激来改善这些不良后果。这项研究很重要，因为表征和识别与烧伤诱导的肝细胞凋亡和内质网应激相关的分子机制将改善严重烧伤患者的临床护理。