Decision points to enter and exit the human cell cycle

 描述(申请人提供)：与癌症、免疫反应、伤口愈合和神经退化相关的疾病通常是由特定类型的人类细胞增殖不足或过度引起的。在正常情况下，这些细胞必须强有力地控制它们是否以及何时增殖，以维持和修复功能组织。虽然人们对细胞如何退出细胞周期知之甚少，但进入细胞周期的决定通常被称为“限制点”，在这个点上，生长因子可以被去除，而细胞仍然进入并完成细胞周期。然而，我们最近的单细胞数据分析表明，这一根本上重要的决定是由不同的机制做出的，涉及细胞周期启动和最终细胞周期承诺步骤。我们的工作将利用自动化的单个活细胞和固定细胞分析，使用生物传感器和活性选择性抗体来测量关键的细胞周期调节事件，并剖析细胞周期进入和退出的控制电路。我们的最终目标是开发和验证细胞周期进出的定量模型。这项拟议工作的成果将是识别、表征和模拟关键的增殖控制点，这些控制点可以用于治疗癌症、免疫反应、伤口愈合以及神经退行性疾病等疾病。对于许多与生长相关的疾病，治疗可能会涉及调控特定细胞类型的增殖速度的策略。此外，我们的工作将为细胞周期和癌症研究社区提供实验和建模工具，以研究不同细胞类型中的细胞特定细胞周期控制。

 DESCRIPTION (provided by applicant): Diseases associated with cancer, immune responses, wound healing, and neurodegeneration are often caused by insufficient or excessive proliferation of particular human cell types. Under normal conditions, such cells have to robustly control if and when they proliferate to maintain and repair functioning tissues. While little is known about how cells exit the cell cycle, the decision to enter the cell cycle is often referred t as a "restriction point", a point where growth factors can be removed and cells still enter and complete the cell cycle. However, our recent single cell data analysis suggests that this fundamentally important decision is made by a different mechanism involving a cell cycle priming and a final cell cycle commitment step. Our proposed work will make use of automated single live cell and fixed cell analysis using biosensor and activity selective antibodies to measure key cell cycle regulatory events and to dissect the control circuits of cell cycle entry and exit. Our final goal is to develop and validate a quantitative model for cell cycle entry and exit. The outcome of the proposed work will be the identification, characterization and modeling of critical proliferation control points that can be exploited therapeutically to treat diseases suh as cancer, immune responses, wound healing, as well as neurodegenerative diseases. For many growth associated diseases, treatment will likely involve strategies to regulate the rate of proliferation of specific cell types. In addition, our work will provide the cell cycle and cancer research communities with experimental and modeling tools to investigate cell specific cell cycle control in different cell types.