Regulation of G0-G1 Transition in Hepatocytes

肝细胞 G0-G1 转变的调节

• 批准号: 7267960
• 负责人: Chinweike Ukomadu
• 金额: $ 23.3万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-10 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267960
• 关键词: Acute; Acute Liver Failure; Biological Assay; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cells; Cyclin-Dependent Kinases; Cyclins; Enzyme-Linked Immunosorbent Assay; Event; Gene Expression Profiling; Gene Targeting; Genes; Goals; Hepatocyte; Injury; Knowledge; Label; Liver; Liver Regeneration; Liver cell necrosis; Metabolic; Molecular; Natural regeneration; Organ; Partial Hepatectomy; Phase; Phosphotransferases; Physiological; Play; Process; Proliferating; Proteins; Rattus; Regulation; Retinoblastoma Protein; Rodent; Role; Serum; Small Interfering RNA; Starvation; Testing; Toxin; Trauma; Virus; base; cdc Genes; cell type; cyclin C; design; hepatoma cell; novel; outcome forecast; research study; therapeutic target

DESCRIPTION (provided by applicant): During liver regeneration, quiescent hepatocytes reenter the cell cycle, proliferate and repopulate the diseased liver. This process is observed in many forms of acute liver injury specifically those caused by viruses, toxins and trauma. Therefore, prognosis in acute liver failure often depends on the ability of proliferation to outlast liver cell necrosis. The long-term objective of the studies outlined here is to use recent knowledge of events that regulate exit from quiescence to identify liver specific targets in the initiation of liver regeneration. The first aim of the study is to evaluate for novel cyclin dependent kinase activities that regulate the transition from quiescence to active cell cycling. We believe that cyclin dependent kinase activities that precede the canonical Gi cyclins are important in transiting from G0 to GI during the regenerative process. The second aim of the study is to design a siRNA based screen that targets genes up regulated in the priming phase of liver regeneration. The goal is to identify genes whose products are necessary for cycle progression. Our hope is to identify physiologically relevant molecules that can be therapeutic targets for enhancement of liver proliferation. A cell based assay using H35 rat liver cell line, which can undergo the transition from quiescence to cell cycle reentry, will be used for both lines of inquiry.

描述（由申请人提供）：在肝脏再生过程中，静止的肝细胞重新进入细胞周期，增殖并重新填充患病肝脏。在许多形式的急性肝损伤中都可以观察到这一过程，特别是由病毒、毒素和创伤引起的急性肝损伤。因此，急性肝功能衰竭的预后通常取决于增殖抵抗肝细胞坏死的能力。这里概述的研究的长期目标是利用调节退出静止事件的最新知识来确定肝再生启动中的肝脏特定目标。该研究的第一个目的是评估调节从静止到活跃细胞周期转变的新型细胞周期蛋白依赖性激酶活性。我们认为，先于典型 Gi 细胞周期蛋白的细胞周期蛋白依赖性激酶活性对于再生过程中从 G0 到 GI 的转变非常重要。该研究的第二个目标是设计一种基于 siRNA 的筛选，针对肝再生启动阶段上调的基因。目标是识别其产物对于周期进展所必需的基因。我们的希望是确定生理相关分子，这些分子可以作为增强肝脏增殖的治疗靶点。使用 H35 大鼠肝细胞系进行的基于细胞的测定，可以经历从静止到细胞周期再进入的转变，将用于这两种研究。