MASTL kinase activity in megakaryocyte differentiation

巨核细胞分化中的 MASTL 激酶活性

• 批准号: 7148402
• 负责人: Helen Janette Johnson
• 金额: $ 12.91万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148402
• 关键词: biological signal transduction; cell cycle; cell differentiation; cell growth regulation; enzyme activity; enzyme substrate; genetic regulation; genetically modified animals; hematopoiesis; immunoprecipitation; laboratory mouse; mass spectrometry; megakaryocytes; microtubule associated protein; phosphorylation; posttranslational modifications; protein localization; protein protein interaction; protein structure function; yeast two hybrid system; zebrafish

DESCRIPTION (provided by applicant): The overall objectives of this project are to gain insight into the mechanism by which the newly identified microtubule associated serine/threonine kinase-like molecule, MASTL regulates terminal differentiation of megakaryocytes, as well as to provide the applicant, Dr. Jan Johnson with the scientific tools and career development necessary for a successful career in Basic Science Research. During the next five years, Dr. Johnson will follow a research career development plan consisting of a program of educational sessions and a laboratory-based research prject under the sponsorship of Drs. Diana Gilligan and Neil Josephson and will have the consulting guidance of Drs. Jonathan Drachman, Kenneth Kaushansky, and Barry Paw. The research plan is to define the molecular signaling mechanisms of the specific serine/theronine kinase MASTL during hematopoeisis in order to better understand the differentiation of megakaryocytes. Megakaryocytes arise from a common hematopoeitic stem cell, commit to a megakaryocytic lineage, mature in the bone marrow of mammals and finally produce platelets for circulation. A tightly regulated maturation of megakaryocytes is maintained to control the numbers of circulating platelets in an organism. A single point mutation was identified in the MASTL kinase in a family suffering with an inherited autosomal dominant thrombocytopenia. This observation has provided evidence for the involvement of this novel kinase in the megakaryocytopoeisis process. The specific aims of this research proposal are: 1) Characterize the MASTL protein expression pattern, kinase activity, and modifications in the megakaryocytic cells as they progress through maturation, 2) Determine the role of MASTL in hematopoeisis model systems, and 3) Identify MASTL kinase substrates in megakaryocyte development. Although these specific aims represent an ambitious goal, the variety of experimental methods and approaches will help develop the breadth of Dr. Johnson's scientific experience as well as generate important data regarding the little understood process of terminal megakaryocyte differentiation which may lead to novel approaches for treating both induced as well as inherited thrombocytopenia.

描述（由申请人提供）： 该项目的总体目标是深入了解新近鉴定的微管相关的丝氨酸/苏氨酸激酶样分子的机制，MASTL调节了巨核细胞的最终差异化，并为申请人提供了扬·约翰逊（Jan Johnson）博士，并为基础科学研究成功提供了科学工具和职业发展。在接下来的五年中，约翰逊博士将遵循一项研究职业发展计划，该计划包括一个教育课程和DRS赞助的基于实验室的研究计划。戴安娜·吉利根（Diana Gilligan）和尼尔·约瑟夫森（Neil Josephson），并将提供博士的咨询指导。乔纳森·德拉克曼（Jonathan Drachman），肯尼斯·考山斯基（Kenneth Kaushansky）和巴里·帕（Barry Paw）。 该研究计划是定义血肿过程中特定丝氨酸/丁氨酸激酶MASTL的分子信号传导机制，以便更好地了解巨核细胞的分化。巨核细胞由常见的造血干细胞产生，致力于巨核细胞谱系，在哺乳动物的骨髓中成熟，最后产生血小板进行循环。保持严格调节的巨核细胞成熟，以控制生物体中循环的血小板的数量。在患有遗传常染色体显性血小板减少症的家族中，在MASTL激酶中鉴定出一个点突变。这一观察结果为这种新型激酶参与巨核细胞的过程提供了证据。该研究建议的具体目的是：1）表征MASTL蛋白表达模式，激酶活性和巨核细胞通过成熟而进行的修饰，2）确定MASTL在血小胞膜模型模型系统中的作用，以及3）识别MASTL激酶在Megakakarakaryocyte发育中的MASTL激酶底物。尽管这些具体目标代表了一个雄心勃勃的目标，但各种实验方法和方法将有助于发展约翰逊博士的科学经验的广度，并生成有关少量理解的末端巨核细胞分化过程的重要数据，这可能会导致治疗诱导的以及遗传性血栓细胞的新方法。