CYCLIN DEPENDENT KINASES 2 AND 4 AND T CELLS

在细胞周期中协调进入和进行是关键的 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之一可以交替地导致 细胞死亡或肿瘤。在细胞周期中传递的保真度 和细胞复制在很大程度上依赖于监管网络 其关键成分是由细胞周期蛋白成员组成的蛋白激酶 依赖激酶(CDK)家族与特定的细胞周期蛋白结合。的目标 这项提案是为了界定在G0-G1和 正常人G1-S的转变及其进展过程 淋巴细胞。这些实验将包括一种多层方法，使用 用于调节细胞周期停滞的药物或生物制剂 在规定的阶段，或作为特定的激动剂或拮抗剂 研究中的单个蛋白质。此应用程序建议支持 通过临床研究人员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 一次传统的博士后经历，让他重新认识自己 熟悉实验室技术，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相关的活动 活动包括每周的实验室会议、研讨会和日记 俱乐部；全研究所正在进行的研究研讨会；以及双周小组 周期会议。这些论坛将提供正式和非正式的 他将有机会讨论他的研究和 与细胞生物学相关的当代话题。这一阶段将设计为 使莫迪亚诺博士能够完善研究和沟通技能，如 以及进行必要的集中和有纪律的思考 在血液病理学和细胞生长领域的独立研究 监管。在阶段I开始的研究将继续到阶段Il， 这也将为莫迪亚诺博士提供一个过渡期 他自己的独立研究。 这个项目的具体目标是：L)确定动力学， 以及信号要求(即抗原或细胞因子受体- 依赖于CDK2和CDK4在T细胞中的表达和活性 细胞，以及2)确定CDK2和CDK4在G1进入过程中的确切作用 以及通过基因操作在淋巴细胞中的进展。

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.