THE ROLE OF PL3K IN THROMBOPOIETIN SIGNALING

（改编自申请人摘要）本K 08提案概述了一项研究计划 旨在给申请人艾米·E·格迪斯，科学训练和 职业发展必要的成功职业生涯在学术医学和 基础科学 拟议的研究将描述以下方面的作用： 磷脂酰肌醇3-激酶（P13 K）在细胞存活和增殖中的作用 血小板生成素（TPO）。 TPO是巨核细胞的主要调节因子- 细胞（MK）发育并在一般造血中起重要作用， 但它的受体Mpl发出信号刺激细胞的机制 存活和增殖还不完全清楚。 我们的初步数据 提示P13 K在这些过程中的作用。 该提案概述了一项战略， 结合使用激酶抑制剂和诱导表达显性 负激酶，以确定P13 K途径的重要元件 因为其在介导响应TPO的存活和增殖中的功能。 此外，还将研究细胞凋亡和增殖中的几种候选途径。 通过TPO评估P13 K依赖性调节。 最后，血小板 将评估降低药物阿那格雷的潜在干扰 通过TPO进行P13 K信号转导。 拟议的研究将涉及表达Mpl的 细胞系以及原代鼠MK祖细胞。 的结果予以 研究将有助于更好地了解TPO的机制， 促进细胞存活和增殖的信号。 TPO的表征 信号传导对于理解正常的MK发育至关重要， 了解血小板生成的治疗性调节的意义， 涉及TPO或阿那格雷的临床使用的实例。 大学 华盛顿为这项提议提供了一个强大的研究环境， 从事相关研究（造血、信号 转导，生物化学，凋亡，分子生物学）， 将提供指导。 正在举办研讨会和课程， 弗雷德哈钦森癌症研究中心 中心提供了额外的资源。 Kaushansky博士和顾问 专门为这项建议的目的而成立的小组将监督 申请人的研究和学术进展。 明确的培训计划是 提出申请人将发展的经验和技能， 作为一名独立的血液学研究者取得成功所必需的。

(Adapted from applicant's abstract) This K08 proposal outlines a research plan designed to give the applicant, Dr. Amy E. Geddis, the scientific training and career development necessary for a successful career in academic medicine and basic science. The proposed research will characterize the role of phosphatidylinositol 3-kinase (P13K) in cell survival and proliferation in response to thrombopoietin (TPO). TPO is the primary regulator of megakaryo- cyte (MK) development and plays an important role in hematopoiesis in general, but the mechanisms by which its receptor, Mpl, signals to stimulate cell survival and proliferation are incompletely understood. Our preliminary data suggest a role for P13K in these processes. The proposal outlines a strategy combining the use of kinase inhibitors and inducible expressed dominant negative kinases to identify elements of the P13K pathway that are important for its function in mediating survival and proliferation in response to TPO. In addition, several candidate pathways in apoptosis and proliferation will be evaluated for P13K-dependent regulation by TPO. Finally, the platelet lowering drug Anagrelide, will be evaluated for its potential interference with P13K signaling by TPO. Proposed studies will involve both Mpl-expressing cell lines as well as primary murine MK progenitors. The results of these studies will lead to a better understanding of the mechanisms by which TPO signals to promote cell survival and proliferation. Characterization of TPO signaling is critical in order to understand normal MK development, and to understand the implications of therapeutic modulation of thrombopoiesis for example involving the clinical use of TPO or Anagrelide. The University of Washington provides a strong research environment for this proposal with many faculty members engaged in related studies (hematopoiesis, signal transduction, biochemistry, apoptosis, molecular biology) whose advise and guidance will be available. There are ongoing seminars and courses in relevant areas, and the proximity of the Fred Hutchinson Cancer Research Center provides an additional resource. Dr. Kaushansky and the advisory panel, formed specifically for the aims of this proposal, will oversee the applicant's research and academic progress. A defined plan of training is presented in which the applicant will develop the experience and skills necessary for success as an independent investigator in Hematology.