Wnt signaling in hepatocyte homeostasis

描述(申请人提供)：在美国，终末期肝病是导致死亡的主要原因。目前，肝移植是治疗终末期肝病的唯一有效方法。肝细胞移植是一种有吸引力的治疗选择。要实现这种治疗潜力，需要了解肝细胞周转是如何维持和调节的。在许多组织中，Wnt蛋白家族作为维持组织干细胞的利基信号，在调节体内平衡方面发挥着关键作用。我们已经确定了在肝脏中作为干细胞的一组独特和新颖的肝细胞。这些细胞自我更新，是二倍体的，不像大多数多倍体的成熟肝细胞，增殖速度比成熟肝细胞快，并产生后代，随着时间的推移取代肝小叶中的整个肝细胞群。重要的是，这些祖细胞存在于正常肝小叶中心周围，不依赖于损伤，因此不同于损伤诱导的卵圆形细胞和Lgr5+细胞。我们建议进一步研究这些细胞的特性，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，并可能导致在使用肝细胞治疗终末期肝病方面的重大进展。建议的研究是王小龙博士导师临床科学家发展奖(K08)的核心组成部分。这笔赠款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，拟议中的研究将为王博士将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，王博士制定了五年的职业发展计划，并组建了一支由肝脏生物学、内皮细胞生物学和干细胞生物学专业的科学家组成的多学科顾问团队。这项研究是在这笔赠款中提出的，加州大学旧金山分校理想的培训环境将确保王博士成功地过渡到一名独立的内科科学家。

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.