Liver Injury and Repopulation by Bone Marrow Stem Cells

骨髓干细胞的肝损伤和再生

• 批准号: 7023332
• 负责人: Eugene Scott Swenson
• 金额: $ 13.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023332
• 关键词: bone marrow; bone marrow transplantation; cell differentiation; cell fusion; cytokine; cytotoxicity; genetically modified animals; green fluorescent proteins; ionizing radiation; laboratory mouse; liver cells; liver disorder; liver regeneration; pathogenic diet; reporter genes; stem cell factor; stem cell transplantation; stem cells; tissue mosaicism; toxin; tyrosinemias

DESCRIPTION (provided by applicant): Chronic liver disease is the 10th leading cause of death in the USA, but liver transplantation is available to only a select few patients. Therefore, non-surgical alternatives are urgently needed. Surprisingly, adult bone marrow contains cells capable of engrafting the liver and treating disease. Detailed understanding of this phenomenon is necessary to advance the use of bone marrow stem cells for liver disease in humans. It has been hypothesized that injured liver releases cytokine signals to the bone marrow, stimulating the release of stem cells into the circulation and recruiting them to damaged liver, where they engraft and become liver cells. The studies proposed here are designed to determine which types and degrees of liver damage promote engraftment and differentiation of bone marrow cells into functional liver cells. The FAH knockout mouse is a model of a human liver disease called hereditary tyrosinemia, which affects children and requires liver transplantation. Cells from normal bone marrow can replace up to half of the diseased liver in FAH mice. The mechanism of repair involves fusion events between marrow-derived cells and diseased liver cells. This model will be compared with experimental liver injuries induced by either the dietary toxin, DDC, or focal liver irradiation. My investigations will address the role of cell-cell fusion, both during normal liver development, and in marrow cell engraftment in the liver. I have 3 years of post-doctoral research experience, and will shortly be completing my training in gastroenterology and hepatology. This application for the mentored K08 award is submitted with the goal of providing me with the further experience and training necessary to function as an independent investigator in hepatology. I will work under the sponsorship of Dr. Diane Krause, a leader in the field of bone marrow transplantation and stem cell differentiation. Her mentoring has enabled her previous fellows to pursue successful academic careers.

描述（由申请人提供）： 慢性肝病是美国第十大死亡原因，但只有少数患者可以使用肝移植。因此，迫切需要非手术替代方案。令人惊讶的是，成年骨髓含有能够雕刻肝脏和治疗疾病的细胞。对这种现象的详细理解对于推进人类肝脏疾病的骨髓干细胞的使用是必要的。据推测，受伤的肝脏将细胞因子信号释放到骨髓中，刺激干细胞进入循环中，并将其募集到受损的肝脏，在那里它们植入并成为肝细胞。此处提出的研究旨在确定哪些类型和程度的肝脏损伤可促进骨髓细胞植入和分化为功能性肝细胞。 FAH基因敲除小鼠是一种称为遗传性酪氨酸的人肝病的模型，它影响儿童并需要肝移植。来自正常骨髓的细胞可以代替FAH小鼠中多达一半患病的肝脏。修复机制涉及骨髓来源细胞与患病细胞之间的融合事件。该模型将与饮食毒素，DDC或局灶性肝脏照射引起的实验性肝损伤进行比较。我的研究将探讨在正常肝发育过程中以及肝脏植物中细胞细胞融合的作用。我有3年的博士后研究经验，很快就会完成我在胃肠病学和肝病学方面的培训。该指导K08奖的该申请的目的是为我提供进一步的经验和培训，以作为肝病独立研究者的运作所必需的培训。我将在戴安娜·克劳斯（Diane Krause）博士的赞助下工作。她的指导使她以前的研究员能够从事成功的学术职业。