Decision points to enter and exit the human cell cycle

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 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.