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.

慢性肝病是美国的第十个主要死因，但肝移植可用于 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 骨髓包含能够雕刻肝脏和治疗疾病的细胞。详细的理解 这种现象对于推进人类肝脏疾病的骨髓干细胞的使用是必要的。 已经假设受伤的肝脏将细胞因子信号释放到骨髓，刺激了 将干细胞释放到循环中，并将其招募到肝脏受损的肝脏，在那里植入和 成为肝细胞。此处提出的研究旨在确定肝脏的类型和程度。 损伤可促进骨髓细胞植入和分化为功能性肝细胞。法 淘汰小鼠是人类肝病的模型，称为遗传性酪氨酸血症，会影响儿童 需要肝移植。来自正常骨髓的细胞最多可以更换一半的患病 肝脏中的肝脏。维修机制涉及骨髓衍生的细胞之间的融合事件和 患病的肝细胞。该模型将与由任何一员诱导的实验性肝损伤进行比较 饮食毒素，DDC或局灶性肝脏照射。我的调查将解决细胞 - 细胞融合的作用 在正常的切开剂发育和肝脏的骨髓细胞植入期间。 我有3年的博士后研究经验，并且很快就会完成训练 胃肠病学和肝病学。该指导K08奖的申请的目标是 为我提供进一步的经验和培训，以作为独立调查员的工作 肝病学。我将在骨髓领域的领导者黛安·克劳斯（Diane Krause）的赞助下工作 移植和干细胞分化。她的指导使她以前的研究员能够追求 成功的学术职业。