THE ROLE OF PL3K IN THROMBOPOIETIN SIGNALING

PL3K 在血小板生成素信号传导中的作用

• 批准号: 6597567
• 负责人: AMY E GEDDIS
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6597567
• 关键词: apoptosis; biological signal transduction; cell proliferation; density gradient ultracentrifugation; enzyme activity; flow cytometry; gel mobility shift assay; immunoprecipitation; laboratory mouse; mitogen activated protein kinase; northern blottings; p53 gene /protein; phosphatidylinositol 3 kinase; phosphorylation; polymerase chain reaction; protein structure function; thrombopoietic factor; tissue /cell culture; western blottings

(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.

(改编自申请人的摘要)这份K08提案概述了一项研究计划 旨在为申请者艾米·E·盖迪斯博士提供科学培训和 在学术医学和医学领域取得成功所必需的职业发展 基础科学。这项拟议的研究将表征 磷脂酰肌醇3-激酶(P13K)在细胞存活和增殖中的作用 对血小板生成素(TPO)的反应。TPO是Megakaryo的主要调节器- 细胞(MK)的发育，在一般的造血中起着重要的作用， 但它的受体MPL发出信号刺激细胞的机制 人们对生存和增殖的了解还不完全。我们的初步数据 建议P13K在这些过程中扮演一个角色。该提案概述了一项战略 结合使用激酶抑制剂和诱导型显性表达 负性激酶用于识别P13K途径中重要的元件 其在调节TPO反应中的存活和增殖中的作用。 此外，在细胞凋亡和增殖中的几个候选途径将是 通过TPO评估P13K依赖的调节。最后，血小板 降压药阿格列德将接受潜在干扰评估 TPO介导的P13K信号转导。拟议的研究将涉及两种MPL的表达 细胞系以及原代小鼠MK祖细胞。这些研究的结果 研究将有助于更好地理解TPO 促进细胞存活和增殖的信号。TPO的表征 为了理解正常的MK发育，信号传递是至关重要的 了解治疗调节血栓生成的意义 涉及TPO或阿格列德临床使用的例子。伊利诺伊大学 华盛顿为这项提议提供了强有力的研究环境，有许多 从事相关研究(造血、信号)的教职员工 转导、生物化学、细胞凋亡、分子生物学)，其建议和 将提供指导。在中国有正在进行的研讨会和课程 相关地区，以及弗雷德·哈钦森癌症研究中心的邻近 中心提供了额外的资源。考尚斯基博士和他的建议 专门为这项提案的目标而成立的小组将监督 申请人的研究和学术进展情况。一个明确的培训计划是 申请者将在其中发展经验和技能 在血液学领域成为一名成功的独立研究者所必需的。