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主要公共卫生问题。 有证据表明，如果不去除病因或愈合受到干扰，肝损伤可能会持续存在。 严重急性肝损伤的缓解能力受损可导致危重疾病、肝功能衰竭和死亡。患者 持续性肝损伤表现为慢性肝病，可进展为肝硬化和肝癌。因此， 提高我们对如何保护肝脏免受损伤以及肝脏潜在机制的了解至关重要 伤口愈合除了肝脏疾病的发病机制和病因之外。先前的研究表明 肝细胞凋亡是各种肝脏相关临床病症（例如肝细胞癌）的深刻病理特征。 缺血/再灌注、药物性肝损伤以及非酒精性脂肪肝等慢性肝病 疾病。迄今为止，尚不清楚肝脏如何从细胞凋亡相关的肝损伤中恢复以及什么 分子可以促进肝脏从细胞凋亡相关的肝损伤中再生。在初步研究中，我们 开发了一种新型三转基因（3xTg）小鼠模型，即3xTg-iHAP（诱导型肝细胞特异性 凋亡表型）小鼠。我们发现 3xTg-iHAP 小鼠含有一组转基因，用于诱导 肝细胞以特定方式发生凋亡。使用 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，随后通过肝脏再生和愈合 有丝分裂过程。此外，我们发现肝细胞凋亡诱导的炎症损伤与 受损肝细胞附近的肝实质细胞中乳脂球-EGF 因子 8 (MFG-E8) 增加。 MFG-E8 是一种营养糖蛋白。我们和其他人已经证明 MFG-E8 可以保持组织稳态， 防止组织损伤，减轻肠道和胰腺的炎症。近日，有报道称 表明肝脏MFG-E8在减轻脂肪肝和纤维化方面发挥保护作用。但目前仍不得而知 MFG-E8 是否以及如何参与修复肝脏细胞凋亡诱导的炎症损伤 脂肪变性和非脂肪变性条件以及病理状态下肝脏中 MFG-E8 表达的调节方式 肝细胞凋亡相关的炎症损伤和脂肪肝等病症。因此，我们将解决 本次优异奖申请中的这两个基本问题侧重于三个具体目标：(1) 研究MFG-E8在调节肝细胞凋亡诱导的肝脏伤口愈合反应中的作用； (2) 至 阐明肝脏病理生理条件如何影响肝脏中 Mfge8 基因的表达； (3) 至 考察MFG-E8促进肝细胞凋亡严重脂肪肝愈合的治疗效果- 诱发损伤。通过实现这些目标，我们将加深对 MFG-E8 如何促进肝脏的理解 炎症损伤后的再生以及细胞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。我们的研究将阐明新的治疗策略的见解 促进各种病理情况下的肝脏伤口愈合。