Liver Injury and Repopulation by Bone Marrow Stem Cells

骨髓干细胞的肝损伤和再生

• 批准号: 7432494
• 负责人: Eugene Scott Swenson
• 金额: $ 13.43万
• 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/7432494
• 关键词: Accounting; Acetoacetates; Address; Adult; Affect; Allogenic; Andro-Diane; Animals; Appearance; Autologous; Award; Blood; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Transplantation; Cause of Death; Cell Differentiation process; 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; embryonic stem cell; experience; injured; intrahepatic; irradiation; liver transplantation; mouse model; oval cell; peripheral blood; programs; protein expression; repaired; response; response to injury; transgene expression

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因，但只有少数患者可以进行肝移植。因此，迫切需要非手术替代方案。令人惊讶的是，成人骨髓中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在人类肝脏疾病中的应用是必要的。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，在那里它们植入并成为肝细胞。这里提出的研究旨在确定哪些类型和程度的肝损伤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血症的人类肝脏疾病的模型，这种疾病影响儿童并需要肝移植。来自正常骨髓的细胞可以替代 FAH 小鼠中多达一半的患病肝脏。修复机制涉及骨髓来源细胞和患病肝细胞之间的融合事件。该模型将与饮食毒素、DDC 或局部肝脏照射引起的实验性肝损伤进行比较。我的研究将探讨细胞与细胞融合在正常肝脏发育过程中以及在肝脏中骨髓细胞植入过程中的作用。我有 3 年的博士后研究经验，很快就会完成胃肠病学和肝病学的培训。提交这份 K08 指导奖申请的目的是为我提供作为肝病学独立研究者所需的进一步经验和培训。我将在骨髓移植和干细胞分化领域的领导者 Diane Krause 博士的赞助下工作。她的指导使她以前的研究员能够追求成功的学术生涯。