Regulating Hepatic Progenitor Cell Proliferation

描述(由申请人提供)： 尽管干细胞研究取得了进展，但仍然存在许多挑战，包括1)保持干细胞处于增殖状态，2)将其定向到特定的成熟细胞。虽然我们开始了解细胞分化所涉及的过程，但关于这些细胞群体出生后的作用，仍有大量悬而未决的问题。据推测，有细胞内和细胞外信号是大多数干细胞群体继续自我更新所必需的。对选择的干细胞或祖细胞经历增殖和随后分化的途径的进一步理解将为推进组织工程和器官发生领域提供见解。 我们之前已经鉴定出一种能持续到成年期的肝祖细胞。在最初分离肝祖细胞后，在细胞增殖和集落形成之前有一段休眠期。从治疗的角度来看，有必要了解参与调节这些肝祖细胞的增殖和存活的途径和中间介质，以努力开发临床应用。这项研究计划中提出的一系列实验将扩大我们对刺激和/或抑制肝祖细胞增殖的关键信号的理解。我们的具体目标如下：(1)研究肝祖细胞的增殖，并研究细胞周期蛋白、细胞周期蛋白依赖性蛋白和细胞周期蛋白激酶抑制物在细胞增殖中的作用；(2)研究细胞内介质包括RAS、p38MAPK、MEK 1/2、ERK 1/2、AKT、p70S6K和磷脂酰肌醇3-激酶(PI3K)在调节肝祖细胞周期进程和增殖中的作用；以及(3)研究抑制性细胞周期介质对肝祖细胞增殖的下游影响。 我们对成人来源的肝祖细胞群体的研究是理解干细胞亚群如何转化为治疗的关键步骤。为了开发新的临床策略，我们需要了解触发这些细胞生长并导致它们成熟为功能细胞的信号通路。

DESCRIPTION (provided by applicant): Despite progress in stem cell research numerous challenges persist including 1) maintaining the stem cells in a proliferative state and 2) directing their commitment into a specific mature cell. While we are beginning to understand the processes involved in cell differentiation there is a large body of unanswered questions with respect to the post-natal role of these cellular populations. It is postulated that there are intra- and extracellular signals that are necessary for most stem cell populations to continue self-renewal. Further comprehension into the pathways by which a select stem or progenitor cell undergoes proliferation and subsequent differentiation will provide insights into advancing the field of tissue engineering and organogenesis. We have previously identified a hepatic progenitor cell that persists into adulthood. After initially isolating the hepatic progenitor cell there is a period of dormancy prior to cell proliferation and colony formation. From a therapeutic standpoint it is necessary to understand the pathways and intermediate mediators involved with regulating proliferation and survival of these hepatic progenitor cells in an effort to develop clinical applications. The proposed series of experiments in this research plan will broaden our understanding of critical signals involved in stimulating and/or inhibiting hepatic progenitor cell proliferation. Our specific aims are as follows: (1) Study hepatic progenitor cell proliferation and characterize the role of cyclin proteins, cyclin dependent kinases and cyclin kinase inhibitors during proliferation; (2) Study the role of intracellular mediators including Ras, p38 mitogen-activated protein kinase (p38MAPK), MEK 1/2, ERK 1/2, AKT, p70s6k, and phosphoinositide 3-kinase (PI3K) in regulating cell cycle progression and proliferation of hepatic progenitor cells; and (3) Study downstream effects of inhibitory cell cycle mediators on hepatic progenitor cell proliferation. Our research efforts with an adult derived liver progenitor cell population are critical steps in understanding how stem cell subpopulations can be translated into therapies. To develop novel clinical strategies we need to understand the signaling pathways that trigger the growth of these cells and leads to their maturation into functional cells.