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末期肝病的重要病因，表征了炎症，脂肪积累和纤维化。由于诸如器官移植之类的传统治疗选择不是很成功，因此非传统疗法（包括使用肝祖细胞（HPC））提供了一种有趣的替代方法。 HPC的增殖和分化似乎是由两个关键因素（肝功能不全和成熟肝细胞复制的能力降低）引起的。在这里，使用两种模型的HSC增殖模型，一种是由胸藻蛋白A（CONA）引起的炎症，第二次是由四氯化碳（CCI4）引起的纤维化，每种均随后进行了部分肝切除术，我们将首先确定损伤的类型是否影响HPC的差异层面。接下来，由于酒精性肝病（ALD）因脂肪肝而变得复杂，因此我们将确定脂肪因成熟肝细胞而降低而响应损伤的成熟肝细胞增殖的能力，对这些模型中的HPC增殖具有。假设脂肪的积累将通过抑制炎症或纤维化和再生肝脏内的正常肝细胞功能和增殖来促进内源性HPC增殖。