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)完成我的博士后研究第四年。我的职业目标是：开发一个研究发育信号如何控制细胞周期退出的研究项目，在未来两年内在一家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NIH或其他来源获得独立资金。为了实现这些目标，我制定了一个独立的研究和职业发展计划，并将从2008年秋季开始寻找工作。我的研究计划的目标是确定末端分化信号如何控制细胞周期机制，以诱导和维持稳定的有丝分裂后状态。我测试了这样的假设，即分化信号通过抑制E2F和/或Cyclin E的活性来启动细胞周期退出，但通过并行抑制两者来稳定地维持退出，从而扰乱通常存在于两者之间的正向调控循环。这确保了细胞周期退出对单个细胞周期因子的去调节是强大的，并在肿瘤发生中以某种方式被绕过。虽然这一假说是基于我之前对果蝇所做的工作，但在这里提出的研究中，我结合了果蝇和哺乳动物细胞的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激动人心的独立研究项目，研究细胞周期退出。这里提出的研究利用了我在布鲁斯·埃德加博士的实验室中获得的以果蝇作为模式生物的专业知识，但也需要建立一种新系统的专业知识，即哺乳动物细胞的体外分化。为了帮助我在研究中发展这一新方面，我聘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，我们实验室的近距离将允许在这个项目的指导阶段进行广泛的互动。 相关性：细胞分裂失控是癌症的一个标志。我的研究解决了成熟细胞如何阻止细胞周期以防止不适当的分裂。我提议的研究将识别信号，当被激活时，向成熟细胞发出错误的方向，并导致过度分裂，模仿癌症。通过了解细胞分裂是如何被不恰当地指导的，我们希望为癌症的治疗找到新的靶点。

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.