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.

在美国和VA医疗保健系统中，与肝损伤相关的疾病仍然是一个主要的公共卫生问题。 有证据表明，如果未去除任何一种病因或愈合，肝损伤可能会持续存在。 解决严重急性肝损伤的障碍会导致危急疾病，肝衰竭和死亡。患者 持续性肝损伤显示慢性肝病，可以发展为肝硬化和肝癌。因此， 至关重要的是要促进我们有关如何保护肝脏免受损伤和肝内机制的知识 除了肝病的发病机理和病因外，伤口愈合。先前的研究表明 肝细胞凋亡是各种与肝有关的临床状况（例如肝脏）的深刻病理特征 缺血/再灌注，药物诱导的肝损伤和慢性肝病，例如非酒精脂肪肝 疾病。最新的是，从与凋亡相关的肝损伤和什么 分子可以促进肝脏因凋亡​​相关肝损伤而再生。在初步研究中，我们 开发了一种新型的三重转基因（3XTG）小鼠模型，即3xtg-ihap（诱导型肝细胞特异性 凋亡表型）小鼠。我们表明3XTG-IHAP小鼠携带一组转基因，用于诱导 特定于肝细胞的凋亡。使用3XTG-IHAP小鼠，我们发现瞬时肝细胞 凋亡随后导致肝炎性损伤，然后通过肝脏再生和通过 有丝分裂过程。此外，我们发现肝细胞凋亡引起的炎症损伤与 随着牛奶脂肪球-EGF因子8（MFG-E8）的增加，附近的肝实质细胞损坏了肝细胞。 MFG-E8是一种营养糖蛋白。我们和其他人表明，MFG-E8保留组织稳态， 预防组织损伤，减轻肠和胰腺的炎症。最近，有报道 肝MFG-E8在衰减脂肪肝和纤维化方面起保护作用。但是，它仍然未知 MFG-E8是否以及如何参与凋亡引起的炎症性损伤的肝脏的修复 脂肪变性和非steatosis条件以及如何在病理学中调节肝脏中MFG-E8的表达 诸如肝细胞凋亡相关炎症损伤和脂肪肝等疾病。因此，我们将解决 这两个基本问题在此功绩奖中的这两个基本问题，重点关注三个具体目标：（1） 研究MFG-E8在调节肝细胞凋亡引起的肝伤口愈合反应中的作用； （2）至 阐明肝病生理状况如何影响肝脏中的MFGE8基因表达。 （3）到 检查MFG-E8对促进肝细胞凋亡的严重脂肪肝愈合的治疗作用 - 诱发受伤。通过实现这些目标，我们将进一步了解MFG-E8如何促进肝脏 炎症损伤后的再生以及诸如凋亡相关肝损伤等病理状况如何 脂肪变性调节MFGE8基因表达。我们的研究将阐明对新型治疗策略的见解 在各种病理条件下促进肝伤口愈合。