Mechanisms controlling cell cycle exit upon terminal differentiation

描述（由申请人提供）：我目前正在弗雷德哈钦森癌症研究中心（FHCRC）完成我的第四年博士后研究。我的职业目标是：开发一个研究项目，研究发育信号如何控制细胞周期退出，在未来两年内在一个领先的学术机构获得终身教职，建立一个富有成效的实验室，在那里我指导学生和博士后，并从美国国立卫生研究院或其他来源获得独立资助。为了实现这些目标，我已经制定了一个独立的研究和职业发展计划，并将在2008年秋季开始找工作。我的研究计划的目标是确定终端分化信号如何控制细胞周期机制来诱导和维持稳定的有丝分裂后状态。我测试了分化信号通过抑制E2F和/或Cyclin E活性启动细胞周期退出的假设，但通过并行抑制两者来稳定地维持退出，从而破坏了通常存在于它们之间的正调节环。这确保了细胞周期退出对单个细胞周期因子的去调控是稳健的，并且在肿瘤发生中以某种方式被绕过。虽然这个假设是基于我之前对果蝇的研究，但在这里提出的研究中，我在果蝇和哺乳动物细胞中结合了遗传和生化方法来描绘控制细胞周期退出的保守途径。通过利用每个模型系统的独特优势，我努力开发一个创造性和令人兴奋的独立研究项目，研究细胞周期退出。这里提出的研究借鉴了我在Bruce Edgar博士的实验室中获得的将果蝇作为模式生物的专业知识，但也需要建立一个新的系统的专业知识，即哺乳动物细胞的体外分化。为了帮助我发展我研究的这个新方面，我邀请了两位专家与我的主要导师布鲁斯·埃德加共同指导我。他们是造血细胞终末分化专家史蒂夫·柯林斯博士和哺乳动物细胞周期领域的著名研究员詹姆斯·罗伯茨博士。两人都是FHCRC的教员，我们的实验室离得很近，在这个项目的指导阶段，我们可以进行广泛的互动。

DESCRIPTION (provided by applicant): I am currently completing my fourth year as a post-doctoral fellow at the Fred Hutchinson Cancer Research Center (FHCRC). My career goals are to: develop a research program examining how developmental signals control cell cycle exit, secure a tenure-track faculty position in a leading academic institution within the next 2 years, build a productive lab where I mentor students and postdocs, and obtain independent funding from the NIH or other sources. Toward achieving these goals, I have developed an independent research and career development plan, and will engage in a job search beginning in the fall of 2008. The goal of my research plan is to determine how terminal differentiation signals control the cell cycle machinery to induce and maintain a stable post-mitotic state. I test the hypothesis that differentiation signals initiate cell cycle exit by inhibiting E2F and/or Cyclin E activities, but stably maintain exit by repressing both in parallel, thereby disrupting the positive regulatory loop that normally exists between them. This ensures that cell cycle exit is robust to the de-regulation of a single cell cycle factor and is somehow bypassed in tumorigenesis. While this hypothesis is based upon my previous work in Drosophila, in the research proposed here, I use a combination of genetic and biochemical approaches in Drosophila and mammalian cells to delineate the conserved pathways that control cell cycle exit. By taking advantage of the unique benefits of each model system I strive to develop a creative and exciting independent research project examining cell cycle exit. The research proposed here draws upon the expertise I have gained in Dr. Bruce Edgar's lab in using Drosophila as a model organism, but also requires building expertise with a new system, in vitro differentiation of mammalian cells. To aid me in developing this new aspect to my research I have enlisted two experts to co- mentor me along with Bruce Edgar, my primary mentor. They are, Dr. Steve Collins, an expert in terminal differentiation of hematopoietic cells and Dr. James Roberts, an eminent researcher in the mammalian cell cycle field. Both are faculty at the FHCRC, and the close proximity of our labs will allow extensive interactions during the mentored phase of this project. RELEVANCE: Uncontrolled cell division is a hallmark of cancer. My research addresses how mature cells block the cell cycle to prevent inappropriate division. My proposed research will identify signals that when activated, give the wrong directions to mature cells and cause excessive division, mimicking cancer. By understanding how cell division can be improperly instructed, we hope to identify new targets for the treatment of cancer.