Alcoholic Liver Diseases: Damage, Repair and Stem Cell Regeneration

酒精性肝病：损伤、修复和干细胞再生

• 批准号: 8102173
• 负责人: ZHAOLI SUN
• 金额: $ 36.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102173
• 关键词: Alcohol abuse; Alcoholic Liver Diseases; Alcohols; Animals; Appearance; Blood; Bone Marrow Cells; CXCR4 gene; Cell Count; Cell physiology; Cells; Chronic; Cirrhosis; Common bile duct structure; DNA Adducts; Ethanol; Ethanol toxicity; Extramural Activities; Failure; Fatty Liver; Green Fluorescent Proteins; Hepatic; Interleukin-6; Isoantibodies; Label; Lead; Ligation; Liver; Liver Failure; Liver diseases; Methods; Modeling; Natural regeneration; Organ Donor; Proto-Oncogene Protein c-kit; Rattus; Role; Signal Transduction; Site; Staining method; Stains; Stem cells; Stromal Cell-Derived Factor 1; Testing; The Sun; Tissues; Toxic effect; Transgenic Organisms; Transplantation; Y Chromosome; alcohol exposure; base; feeding; innovation; insight; liver transplantation; non-alcoholic; novel; problem drinker; public health relevance; regenerative; repaired; response; stem; success

DESCRIPTION (provided by applicant): We have found that a small (50%) liver transplant which regenerates rapidly in a normal host, fails to do so in a host subjected to chronic alcohol feeding and postulate that a part of the systemic effects of chronic alcohol abuse is damage to extra-hepatic progenitor cells. Indeed, after five weeks of alcohol feeding the numbers of bone marrow cells staining for c-Kit and CXCR4 are markedly diminished, and these cells contain 8-OHdG, the stable oxidative adduct of DNA. Interestingly, a small liver from an alcohol fed rat transplanted to a normal rat functions well while a whole liver fails suggesting that regenerative signals from the small damaged liver are sufficient to rescue the graft when the host is normal. The messages responsible for the recruitment of stem cells must be present in the liver exposed to alcohol. Indeed blood levels of IL-6, and tissue levels of stromal cell-derived factor-1 (SDF-1) were found to be normal. Delineation of the cellular mechanisms leading to either success or failure will be assessed with established labels, green fluorescent protein (GFP) transgenic Lewis rats, Y chromosome probes, and alloantibody in the case of Lewis to DA transplants. Comparisons will be made between animals with alcohol liver disease and those with ligation of the common bile duct. The temporal appearance of stem cell abnormalities after these two types of liver insults, and the magnitude of the differences will help distinguish between a direct toxic effect of alcohol on stem cells, and a slow loss of stem cell numbers and function paralleling the course of liver failure. The objective of this proposal is to bring together Dr. Zhaoli Sun's expertise in liver transplantation models and Dr. Bin Gao's expertise in alcoholic liver diseases so that, as a functioning collaborative unit, innovative new therapies based on examinations of extra-hepatic progenitor cell vitality may develop. Further, there is hope that these studies will find application in better usage of the fatty liver for transplantation. This collaborating proposal will provide novel insights into the role of extra-hepatic stem/progenitor cells. PUBLIC HEALTH RELEVANCE: Alcoholic liver disease (ALD) is one of the most common causes of cirrhosis and indication for liver transplantation. Delineation and clarification of how ethanol influences hepatic stem/progenitor cells may lead to new therapies for alcoholic liver disease. The ability to utilize alcoholic livers for transplantation would significantly increase the organ donor pool.

描述（由申请人提供）：我们发现，在正常宿主中快速再生的小块（50%）肝移植在长期酒精喂养的宿主中不能再生，并假设慢性酒精滥用的一部分系统性影响是对肝外祖细胞的损害。确实，在酒精喂养五周后，骨髓细胞c-Kit和CXCR4染色的数量明显减少，这些细胞含有8-OHdG，一种稳定的DNA氧化加合物。有趣的是，将酒精喂养大鼠的小肝脏移植到正常大鼠身上功能良好，而整个肝脏却衰竭了，这表明当宿主正常时，受损小肝脏的再生信号足以挽救移植物。负责干细胞募集的信息必须存在于暴露于酒精的肝脏中。事实上，血液中IL-6的水平和组织中基质细胞衍生因子-1 （SDF-1）的水平都是正常的。对导致成功或失败的细胞机制的描述将通过已建立的标记、绿色荧光蛋白（GFP）转基因Lewis大鼠、Y染色体探针和Lewis to DA移植的同种异体抗体进行评估。将对酒精性肝病动物和胆总管结扎动物进行比较。在这两种类型的肝脏损伤后，干细胞异常的时间外观和差异的大小将有助于区分酒精对干细胞的直接毒性作用，以及与肝衰竭过程平行的干细胞数量和功能的缓慢丧失。该提案的目的是将孙兆立博士在肝移植模型方面的专业知识与高斌博士在酒精性肝病方面的专业知识结合起来，作为一个功能协作单位，基于肝外祖细胞活力检查的创新新疗法可能会发展起来。进一步，这些研究有望在脂肪肝移植中得到更好的应用。这一合作建议将为肝外干细胞/祖细胞的作用提供新的见解。