CYCLIN DEPENDENT KINASES 2 AND 4 AND T CELLS

细胞周期的协调进入和进展对于 所有细胞的正常功能和复制;一个或几个细胞的缺陷 控制细胞周期进程的步骤可以交替地导致 细胞死亡或瘤形成。在细胞周期中传递的保真度 和细胞复制很大程度上依赖于一个调控网络 其关键成分是由细胞周期蛋白 依赖性激酶（CDK）家族与特异性细胞周期蛋白结合。的目标 这个建议是要定义在G 0-G1期间表达的cdk的角色， G1-S转换，以及在正常人中进展至G1期间 淋巴细胞实验将包括一个多层次的方法， 设计用于介导细胞周期停滞的药理学或生物学试剂 在限定的阶段，或作为特异性激动剂或拮抗剂， 研究中的蛋白质。本申请旨在支持 通过临床研究者的两阶段机制进行这些研究 发展奖。 该项目的培训阶段（第一阶段）将为莫迪亚诺博士提供 传统的博士后经历，让他重新认识自己， 熟悉的实验室技术，并在监督下学习新技术。 环境莫迪亚诺博士还将参加其他与实验室有关的 活动包括每周实验室会议、研讨会和期刊 俱乐部;研究所范围的进展研究研讨会;和双周小组 循环会议。这些论坛将提供正式和非正式的 在那里他将有机会讨论他的研究， 细胞生物学中的相关当代话题。本阶段将设计 让莫迪亚诺博士完善研究和沟通技巧， 以及进行必要的集中和纪律性思维 在血液病理学和细胞生长领域的独立研究 调控第一阶段开始的研究将继续进行到第二阶段， 这也将为莫迪亚诺博士提供一个过渡期， 自己的独立研究。 该项目的具体目标是：1）确定动力学， 以及信令要求（即，抗原或细胞因子受体- 依赖性）的人T细胞中cdk 2和cdk 4的表达和活性 细胞，2）确定cdk 2和cdk 4在G1期进入过程中的确切作用 和淋巴细胞的进展。

Coordinated entry and progression through the cell cycle is critical for normal function and replication of all cells; a defect in one or several of the steps that control cell cycle progression can lead alternatively to cell death or neoplasia. The fidelity of transit through the cell cycle and cellular replication are largely dependent on a regulatory network whose key components are protein kinases composed of members of the cyclin dependent kinase (cdk) family bound to specific cyclins. The objectives of this proposal are to define the roles of cdk's expressed during G0-G1 and G1-S transitions, and during progression though G1 in normal human lymphocytes. The experiments will include a multi-tiered approach using pharmacological or biological agents designed to mediate cell cycle arrest at defined stages, or to act as specific agonists or antagonists of the individual proteins under study. This application proposes to support these studies through the two-phase mechanism of a Clinical Investigator Development Award. The training phase of the project (phase I), will provide Dr. Modiano with a traditional post-doctoral experience to allow him to re-acquaint himself with familiar laboratory techniques and to learn new ones in a supervised environment. Dr. Modiano also will participate in other laboratory-related activities including weekly laboratory meetings, seminars, and journal clubs; Institute-wide Research in Progress seminars; and biweekly cell cycle meetings. These forums will provide both formal and informal settings where he will have the opportunity to discuss his research and pertinent contemporary topics in cell biology. This phase will be designed to allow Dr. Modiano to refine the research and communication skills, as well as the focused and disciplined thinking necessary to conduct independent research in the areas of hemopathology and cell growth regulation. The research started in phase I will continue into phase Il, which also will provide a transition period for Dr. Modiano to initiate his own independent research. The specific aims of this project are to: l) determine the kinetics of, and the signaling requirements (i.e., antigen or cytokine receptor- dependent) for the expression and activity of cdk2 and cdk4 in human T cells, and 2) determine the precise roles of cdk2 and cdk4 during G1 entry and progression in lymphocytes by genetic manipulation.