Wnt signaling in hepatocyte homeostasis

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唯一有效的方法。肝细胞移植是一种有吸引力的治疗方法。实现这种治疗潜力需要了解肝细胞更新是如何维持和调节的。在许多组织中，Wnt家族蛋白通过作为生态位信号维持组织干细胞在调节体内平衡中发挥关键作用。我们已经在肝脏中发现了一种独特的、新颖的肝细胞群，它们可以作为干细胞。这些细胞自我更新，是二倍体，不像大多数多倍体的成熟肝细胞，它们的增殖速度比成熟肝细胞快，并随着时间的推移产生替代肝小叶中整个肝细胞群的后代。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，因此与损伤诱导的卵圆细胞和Lgr5+细胞不同。我们建议进一步研究这些细胞的特征，确定维持它们作为祖细胞的细胞和分子机制，并研究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，并可能导致使用肝细胞治疗终末期肝病的重大进展。建议的研究是Bruce Wang博士获得指导临床科学家发展奖（K08）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进行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研究结果扩展到人类肝脏提供关键的下一步。为了实现这些目标，王博士设计了一个5年的职业发展计划，并组建了一个多学科的科学家咨询团队，专门从事肝脏生物学，内皮细胞生物学和干细胞生物学。该基金提出的研究和UCSF理想的培训环境将确保王博士成功过渡到一个独立的医生-科学家。

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.