Wnt signaling in hepatocyte homeostasis

肝细胞稳态中的 Wnt 信号传导

• 批准号: 9214329
• 负责人: Bruce Mao Zheng Wang
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214329
• 关键词: AXIN2 gene; Advisory Committees; Animals; Area; Biology; Cell Culture Techniques; Cell Therapy; Cell Transplantation; Cells; Cellular biology; Central Vein; Characteristics; Development Plans; Diploidy; Endothelial Cells; Ensure; Environment; Gene Targeting; Goals; Grant; Half-Life; Health; Hepatic lobule; Hepatocyte; Hepatocyte transplantation; Homeostasis; Hour; Human; In Vitro; Injury; LGR5 gene; Label; Lead; Length; Liver; Liver Regeneration; Liver diseases; Lobule; Mentored Clinical Scientist Development Award (K08); Molecular; Morbidity - disease rate; Multipotent Stem Cells; Mus; Patients; Physicians; Play; Polyploidy; Population; Portal vein structure; Production; Proliferating; Property; Protein Family; Replacement Therapy; Research; Scientist; Signal Transduction; Source; Stem cells; Therapeutic; Time; Tissues; Training; Transplantation; United States; WNT Signaling Pathway; Wnt proteins; Work; career development; effective therapy; improved; in vivo; liver transplantation; mortality; mouse model; multidisciplinary; novel; oval cell; progenitor; programs; public health relevance; regenerative; residence; self renewing cell; stem cell biology; stem cell population

DESCRIPTION (provided by applicant): End-stage liver disease is a major cause of mortality in the United States. Currently, liver transplantation is the only effective therapy for end-stage liver disease. An attractive therapeutic alternative is hepatocyte cell transplantation. Realizing that therapeutic potential requires understanding how hepatocyte turnover is maintained and regulated. In many tissues, the Wnt family of proteins plays a key role in regulating homeostasis by serving as niche signals to maintain tissue stem cells. We have identified a unique and novel population of hepatocytes in the liver that act as stem cells. These cells self-renew, are diploid, unlike the mostly polyploid mature hepatocytes, proliferate at a faster rate than mature hepatocytes and generate progeny that replace the entire hepatocyte population in the liver lobule over time. Importantly, these progenitors are present pericentrally in the normal liver lobule, are not dependent on injury and thereby distinct from injury-induced oval cells and Lgr5+ cells. We propose studies to further characterize these cells, determine the cellular and molecular mechanism that maintain them as progenitors and examine whether they can be expanded in culture. The results of these studies will provide a novel frame work for understanding liver homeostasis and may lead to significant advances in the use of hepatocytes for treating end-stage liver disease. The proposed studies are the core components of the Mentored Clinical Scientist Development Award (K08) for Dr. Bruce Wang. The grant is a training vehicle for Dr. Wang to achieve additional scientific training in cell culture, live imagig and hepatocyte transplantation. Also, the proposed studies will provide the critical next step in extending Dr. Wang's animal findings to human liver. To achieve these goals, Dr. Wang has devised a 5-year career development plan and assembled a multidisciplinary advisory team of scientists specializing in liver biology, endothelial cell biology and stem cell biology. The studis proposed in this grant and the ideal training environment at UCSF will ensure Dr. Wang a successful transition to an independent physician- scientist.

描述（由申请人提供）：终末期肝病是美国死亡的主要原因。目前，肝移植是治疗终末期肝病的唯一有效方法。一种有吸引力的治疗替代方案是肝细胞移植。认识到治疗潜力需要了解如何维持和调节肝细胞周转。 在许多组织中，Wnt蛋白家族通过充当维持组织干细胞的生态位信号在调节体内平衡中起关键作用。我们已经确定了一个独特的和新的人口肝细胞在肝脏中作为干细胞。这些细胞自我更新，是二倍体，不像大多数多倍体成熟肝细胞，以比成熟肝细胞更快的速率增殖，并产生随着时间推移取代肝小叶中整个肝细胞群体的后代。重要的是，这些祖细胞存在于正常肝小叶的中心周围，不依赖于损伤，因此不同于损伤诱导的卵圆细胞和Lgr 5+细胞。 我们建议研究进一步表征这些细胞，确定维持它们作为祖细胞的细胞和分子机制，并检查它们是否可以在培养中扩增。这些研究的结果将为理解肝脏稳态提供一个新的框架，并可能导致肝细胞用于治疗终末期肝病的重大进展。 拟定的研究是布鲁斯王博士指导临床科学家发展奖（K 08）的核心组成部分。该基金是王博士在细胞培养、活体成像和肝细胞移植方面获得额外科学培训的培训工具。此外，拟议的研究将为将王博士的动物发现扩展到人类肝脏提供关键的下一步。为了实现这些目标，王博士制定了一个5年的职业发展计划，并组建了一个由肝脏生物学、内皮细胞生物学和干细胞生物学专业科学家组成的多学科咨询团队。本研究计划和UCSF理想的培训环境将确保王博士成功转型为一名独立的医生-科学家。