Liver Injury and Repopulation by Bone Marrow Stem Cells

骨髓干细胞的肝损伤和再生

• 批准号: 7873340
• 负责人: Eugene Scott Swenson
• 金额: $ 5.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-25 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873340
• 关键词: Accounting; Acetoacetates; Address; Adult; Affect; Allogenic; Animals; Appearance; Autologous; Award; Blood; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Transplantation; Cause of Death; Cell Proliferation; Cell Therapy; Cell fusion; Cells; Child; Chimera organism; Chronic; Cytokeratin 8; Cytokine Signaling; Development; Disease; Engraftment; Epithelial; Epithelial Cells; Epithelium; Event; Gastroenterology; Goals; Green Fluorescent Proteins; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Hepatic; Hepatocyte; Hepatology; Human; Injury; Investigation; Kinetics; Knockout Mice; Liver; Liver diseases; Malignant - descriptor; Marrow; Measures; Mediator of activation protein; Mentors; Modeling; Mus; Muscle Fibers; Natural regeneration; Normal Cell; Operative Surgical Procedures; Patients; Phenotype; Ploidies; Polyploidy; Postdoctoral Fellow; Process; Proliferating; Radiation; Recruitment Activity; Reporter; Research; Research Personnel; Role; Signal Transduction; Skeletal Muscle; Stem Cell Factor; Stem cells; System; Testing; Tissues; Toxin; Training; Transplantation; Tyrosinemias; Umbilical Cord Blood; Wild Type Mouse; Work; Y Chromosome; blastocyst; career; cholangiocyte; cytokine; design; developmental plasticity; embryonic stem cell; experience; injured; intrahepatic; irradiation; liver transplantation; mouse model; oval cell; peripheral blood; programs; protein expression; repaired; response; response to injury; stem cell differentiation; transgene expression

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 tiver development, and in marrow cell engraftment in the liver. I have 3 years of post-doctoral research experience, andwill shortly be completing mytraining in gastroenterology and hepatology. This application for the mentored K08 award is submitted with the goal of providing mewith 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.

慢性肝病是美国第十大死因，但肝移植可以 只有少数患者。因此，迫切需要非手术替代方案。令人惊讶的是，成人 骨髓含有能够移植肝脏并治疗疾病的细胞。详细了解 这种现象对于推进骨髓干细胞用于治疗人类肝脏疾病是必要的。 据推测，受损的肝脏向骨髓释放细胞因子信号，刺激 将干细胞释放到循环中并将它们招募到受损的肝脏，在那里它们植入并 变成肝细胞。这里提出的研究旨在确定肝脏的类型和程度。 损伤促进骨髓细胞植入并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血症的人类肝脏疾病的模型，这种疾病会影响儿童 并且需要肝移植。来自正常骨髓的细胞可以替代多达一半的患病骨髓细胞 FAH 小鼠的肝脏。修复机制涉及骨髓来源细胞和骨髓来源细胞之间的融合事件 患病的肝细胞。该模型将与由以下任一因素引起的实验性肝损伤进行比较： 膳食毒素、DDC 或局灶性肝脏照射。我的研究将解决细胞与细胞融合的作用 在正常的肝脏发育过程中以及在肝脏中的骨髓细胞植入过程中。 我有 3 年的博士后研究经验，很快就会完成我的培训 胃肠病学和肝病学。提交此 K08 指导奖申请的目的是 为我提供作为独立调查员所需的进一步经验和培训 肝病学。我将在骨髓领域的领军人物 Diane Krause 博士的赞助下工作 移植和干细胞分化。她的指导使她以前的同事能够追求 成功的学术生涯。