Regulating Hepatic Progenitor Cell Proliferation

调节肝祖细胞增殖

• 批准号: 7359649
• 负责人: DAVID A GERBER
• 金额: $ 7.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7359649
• 关键词: 1-Phosphatidylinositol 4-Kinase; 70-kDa Ribosomal Protein S6 Kinases; Adult; Cell Cycle; Cell Cycle Progression; Cell Differentiation process; Cell Proliferation; Cells; Characteristics; Clinical; Commit; Comprehension; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cyclins; Environment; Hepatic; Liver; MEKs; Mediator of activation protein; Organogenesis; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Population; Process; Proto-Oncogene Proteins c-akt; Research; Role; Series; Signal Pathway; Signal Transduction; Stem Cell Research; Stem cells; Therapeutic; Tissue Engineering; Translating; Undifferentiated; cell growth; clinical application; extracellular; human MAPK14 protein; insight; mitogen-activated protein kinase p38; novel; research study; self-renewal; stem

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.

描述（由申请人提供）： 尽管干细胞研究取得了进展，但仍存在许多挑战，包括1）将干细胞维持在增殖状态和2）将其定向转化为特定的成熟细胞。虽然我们开始了解细胞分化的过程，但关于这些细胞群体的出生后作用，还有大量未回答的问题。据推测，存在对于大多数干细胞群体继续自我更新所必需的细胞内和细胞外信号。进一步理解选择的干细胞或祖细胞经历增殖和随后的分化的途径将为推进组织工程和器官发生领域提供见解。 我们以前已经确定了一个肝祖细胞，持续到成年。在最初分离肝祖细胞之后，在细胞增殖和集落形成之前存在休眠期。从治疗的角度来看，有必要了解参与调节这些肝祖细胞增殖和存活的途径和中间介质，以努力开发临床应用。本研究计划中的一系列实验将拓宽我们对刺激和/或抑制肝祖细胞增殖的关键信号的理解。本研究的具体目的如下：（1）研究肝祖细胞的增殖及细胞周期蛋白、细胞周期蛋白依赖性激酶和细胞周期蛋白激酶抑制剂在肝祖细胞增殖中的作用;（2）研究Ras、p38丝裂原活化蛋白激酶（p38 MAPK）、MEK 1/2、ERK 1/2、AKT、p70 s6 k、和磷脂酰肌醇3-激酶（PI 3 K）在肝祖细胞增殖和细胞周期进程调控中的作用;（3）研究抑制性细胞周期介质对肝祖细胞增殖的下游作用。 我们对成人来源的肝祖细胞群的研究工作是理解干细胞亚群如何转化为治疗方法的关键步骤。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其成熟为功能细胞的信号通路。