Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response

乳脂肪球-EGF因子8与肝细胞凋亡诱导的肝脏创面愈合反应

• 批准号: 10585802
• 负责人: Xiao-Di Tan
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585802
• 关键词: 3xTg-AD mouse; Address; Adult; Alcoholic Liver Diseases; Alcohols; American; Animal Model; Apoptosis; Apoptotic; Area; Attenuated; Award; Caspase; Cause of Death; Cell Death; Cells; Cessation of life; Cirrhosis; Clinical; Critical Illness; Disease; Dose; Doxycycline; EGF gene; Etiology; Event; Face; Fatty Liver; Fibrosis; Functional disorder; Future; Gene Expression; Glycoproteins; Growth Factor; Healthcare Systems; Hepatic; Hepatocyte; Homeostasis; Human; Impairment; Induction of Apoptosis; Inflammation; Inflammatory; Injury; Intestines; Ischemia; Knowledge; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver Regeneration; Liver diseases; MFGE8 gene; Molecular Target; Mus; Natural regeneration; Operative Surgical Procedures; Organ; Pancreas; Partial Hepatectomy; Pathogenesis; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Population; Primary carcinoma of the liver cells; Process; Proliferating; Proteins; Public Health; Published Annual Reports; Reactive Oxygen Species; Regulation; Reperfusion Therapy; Reporting; Research; Role; Signal Transduction; Signaling Molecule; Structure; Therapeutic Effect; Tissue Preservation; Tissues; Transgenes; Transgenic Organisms; Trauma; Tumor Necrosis Factor Ligand Superfamily Member 6; United States; United States Department of Veterans Affairs; United States National Center for Health Statistics; Veterans; Veterans Health Administration; acute liver injury; age group; attenuation; cell injury; chronic liver disease; cytokine; drug induced liver injury; healing; human old age (65+); insight; liver injury; liver ischemia; liver repair; milk fat globule; mortality; mouse model; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; novel therapeutics; repaired; response; stem; stem cells; tissue injury; wound healing

Liver injury-associated diseases remain a major public health problem in the U.S. and VA healthcare system. Evidence shows that liver injury can persist if either etiologic agents are not removed or healing is disrupted. Impaired resolving severe acute liver injury can lead to critical illness conditions, liver failure and death. Patients with persistent liver injury display chronic liver disease which can progress to cirrhosis and liver carcinoma. Thus, it is critical to advance our knowledge about how to protect liver from injury and mechanisms underlying liver wound healing in addition to the pathogenesis and etiology of liver disease. Previous studies show that hepatocyte apoptosis is a profound pathological feature of various liver-related clinical conditions such as liver ischemia/reperfusion, drug-induced liver injury, and chronic liver diseases such as nonalcoholic fatty liver disease. Up to date, it is largely unknown how liver is healed from apoptosis-associated liver injury and what molecules can promote liver to regenerate from apoptosis-associated liver injury. In preliminary studies, we developed a novel triple-transgenic (3xTg) mouse model, namely, 3xTg-iHAP (inducible hepatocyte specific apoptosis phenotype) mice. We showed that 3xTg-iHAP mice harbor a set of transgenes for induction of apoptosis in hepatocyte specific manner. Using 3xTg-iHAP mice, we have found that transient hepatocyte apoptosis subsequently leads to liver inflammatory injury followed by liver regeneration and healing through a mitogenic process. Furthermore, we found that hepatocyte apoptosis-induced inflammatory injury is associated with increase in milk fat globule-EGF factor 8 (MFG-E8) in liver parenchymal cells nearby damaged hepatocytes. MFG-E8 is a trophic glycoprotein. We and others have shown that MFG-E8 preserves tissue homeostasis, protects against tissue injury, attenuates inflammation in intestines and pancreas. Recently, it has been reported that hepatic MFG-E8 plays a protective role in attenuation of fatty liver and fibrosis. However, it remains unknown that whether and how MFG-E8 is involved in repairing liver from apoptosis-induced inflammatory injury in steatosis and non-steatosis conditions and how MFG-E8 expression is regulated in the liver upon pathological conditions such as hepatocyte apoptosis-associated inflammatory injury and fatty liver. Thus, we will address these two fundamental questions in this MERIT award application by focusing on three Specific Aims: (1) To study the role of MFG-E8 in regulation of hepatocyte apoptosis-induced liver wound-healing response; (2) To elucidate how liver pathophysiological conditions influence Mfge8 gene expression in the liver; and (3) To examine the therapeutic effect of MFG-E8 on promoting healing of severe fatty liver from hepatocyte apoptosis- induced injury. By accomplishing these aims, we will advance our understanding of how MFG-E8 promotes liver regeneration upon inflammatory injury and how pathological conditions such as apoptosis-associated liver injury and steatosis regulate Mfge8 gene expression. Our study will elucidate insights into novel therapeutic strategies to promote liver wound healing in various pathological conditions.

肝损伤相关疾病仍然是美国和退伍军人管理局医疗系统的一个主要公共卫生问题。 有证据表明，如果不清除病原体或破坏愈合，肝脏损伤可能会持续。 严重的急性肝损伤会导致严重的病情、肝功能衰竭和死亡。病人 持续性肝损伤表现为慢性肝病，可进展为肝硬变和肝癌。因此， 提高我们对如何保护肝脏免受损伤及其机制的认识是至关重要的。 伤口愈合以及肝脏疾病的发病机制和病因。此前的研究表明， 肝细胞凋亡是各种肝脏相关临床疾病的深刻病理特征，如肝脏 缺血/再灌注、药物性肝损伤和慢性肝病，如非酒精性脂肪肝 疾病。到目前为止，很大程度上还不清楚肝脏是如何从与细胞凋亡相关的肝损伤中愈合的，以及是什么 分子可以促进肝脏从与细胞凋亡相关的肝损伤中再生。在初步研究中，我们 建立了一种新的三重转基因(3xTg)小鼠模型，即3xTg-iHAP(可诱导肝细胞特异性 细胞凋亡表型)小鼠。我们发现3xTg-iHAP小鼠携带一组转基因，可以诱导 肝细胞特异性的细胞凋亡。利用3xTg-iHAP小鼠，我们发现瞬时肝细胞 细胞凋亡随后导致肝脏炎症损伤，随后肝脏再生和愈合，通过 有丝分裂过程。此外，我们还发现肝细胞凋亡诱导的炎性损伤与 随着受损肝细胞附近肝实质细胞乳脂小球-EGF因子8(MFG-E8)表达的增加。 MFG-E8是一种营养糖蛋白。我们和其他人已经证明，MFG-E8保持组织动态平衡， 保护组织免受损伤，减轻肠道和胰腺的炎症。最近，据报道， 说明肝脏MFG-E8对减轻脂肪肝和肝纤维化具有保护作用。然而，它仍然是未知的 MFG-E8是否以及如何参与肝细胞凋亡诱导的炎性损伤修复 脂肪变性和非脂肪变性条件以及MFG-E8在肝脏中的表达在病理上是如何调节的 肝细胞凋亡相关的炎性损伤和脂肪肝等情况。因此，我们将解决 这两个基本问题集中在以下三个具体目标上：(1) 研究MFG-E8在肝细胞凋亡诱导的肝损伤修复反应中的调节作用； 阐明肝脏病理生理状况如何影响肝脏中Mfge8基因的表达；及 从肝细胞凋亡观察MFG-E8促重型脂肪肝愈合的作用 致伤。通过实现这些目标，我们将进一步了解MFG-E8是如何促进肝脏的 炎性损伤的再生和病理条件，如细胞凋亡相关的肝损伤 脂肪变性调节Mfge8基因的表达。我们的研究将阐明对新的治疗策略的见解 在各种病理条件下促进肝脏创面愈合。