Liver Stem Cell Response to Inflammation and Alcohol

肝干细胞对炎症和酒精的反应

• 批准号: 6890904
• 负责人: IAN N HINES
• 金额: $ 4.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890904
• 关键词: alcoholic beverage consumption; alcoholic fatty liver; alcoholic hepatitis; alcoholic liver cirrhosis; carbon tetrachloride; cell proliferation; concanavalin A; disease /disorder model; ethanol; fats; fibrosis; flow cytometry; hepatectomy; immunocytochemistry; immunomagnetic separation; inflammation; laboratory mouse; liver cells; pathology; postdoctoral investigator; stem cells; toxicology

DESCRIPTION (provided by applicant): Alcohol-induced liver injury represents a significant etiology of end-stage liver disease characterized inflammation, fat accumulation, and fibrosis. Because traditional treatment options such as organ transplantation have not been very successful, non-traditional therapies including the use of hepatic progenitor cells (HPC) offer an intriguing alternative. HPC proliferation and differentiation seems to be induced by two critical factors, hepatic insufficiency and a decreased ability of mature hepatocytes to replicate. Here, using two models of HSC proliferation, one initiated by inflammation due to Concanavalin A (ConA) and a second by fibrosis due to carbon tetrachloride (CCI4), each followed by partial hepatectomy, we will first determine whether the type of injury affects the differentiation lineage of HPCs. Next, since alcoholic liver disease (ALD) is complicated by fatty liver, we will determine the effect that fat, due to its reduction in the ability of mature hepatocytes to proliferate in response to injury, has on HPC proliferation in these models. It is hypothesized that fat accumulation will promote endogenous HPC proliferation by inhibition of normal hepatocyte function and proliferation within the inflamed or fibrotic and regenerating liver.

描述（由申请人提供）：酒精诱导的肝损伤代表了以炎症、脂肪蓄积和纤维化为特征的终末期肝病的重要病因。由于器官移植等传统治疗方案并不十分成功，因此包括使用肝祖细胞（HPC）在内的非传统疗法提供了一种有趣的替代方案。HPC增殖和分化似乎是由两个关键因素诱导的，即肝功能不全和成熟肝细胞复制能力下降。在这里，使用两种模型的HSC增殖，一个由炎症引起的刀豆球蛋白A（ConA）和第二个由纤维化引起的四氯化碳（CCl4），每个随后部分肝切除术，我们将首先确定是否损伤的类型影响分化谱系的HPC。接下来，由于酒精性肝病（ALD）并发脂肪肝，我们将确定脂肪的影响，由于其降低成熟肝细胞对损伤的增殖能力，在这些模型中对HPC增殖的影响。据推测，脂肪蓄积将通过抑制正常肝细胞功能以及发炎或纤维化和再生肝脏内的增殖来促进内源性HPC增殖。