MASTL kinase activity in megakaryocyte differentiation

描述（由申请人提供）： 该项目的总体目标是深入了解新发现的微管相关丝氨酸/苏氨酸激酶样分子MASTL调节巨核细胞终末分化的机制，并为申请人Jan约翰逊博士提供在基础科学研究中取得成功所需的科学工具和职业发展。在接下来的五年里，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计划和一个由Diana Gilligan博士和Neil Josephson博士赞助的基于实验室的研究项目，并将得到Jonathan Drachman博士、Kenneth Kaushansky博士和巴里Paw博士的咨询指导。 本研究旨在明确造血过程中特异性丝氨酸/苏氨酸激酶MASTL的分子信号转导机制，以更好地理解巨核细胞的分化。巨核细胞起源于常见的造血干细胞，形成巨核细胞谱系，在哺乳动物的骨髓中成熟，并最终产生用于循环的血小板。维持巨核细胞的严格调节的成熟以控制生物体中循环血小板的数量。在一个患有遗传性常染色体显性血小板减少症的家族中，在MASTL激酶中发现了一个单点突变。这一观察结果提供了证据，这种新的激酶参与巨核细胞凋亡过程。本研究计划的具体目标是：1）表征MASTL蛋白表达模式，激酶活性和巨核细胞成熟过程中的修饰，2）确定MASTL在造血模型系统中的作用，3）鉴定MASTL激酶底物在巨核细胞发育中的作用。虽然这些具体的目标代表了一个雄心勃勃的目标，各种实验方法和途径将有助于发展约翰逊博士的科学经验的广度，以及产生关于终末巨核细胞分化过程的重要数据，这可能导致治疗诱导性和遗传性血小板减少症的新方法。

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.