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Mast1调节巨核细胞终末分化的机制，并为申请人Jan Johnson博士提供在基础科学研究领域取得成功所必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，该计划由戴安娜·吉利根博士和尼尔·约瑟夫森博士赞助的教育课程和以实验室为基础的研究项目组成，并将得到乔纳森·德拉赫曼博士、肯尼斯·考尚斯基博士和巴里·保罗博士的咨询指导。 研究计划是为了更好地了解巨核细胞的分化，确定特定的丝氨酸/丝氨酸激酶Mast1在造血过程中的分子信号机制。巨核细胞来源于一种常见的造血干细胞，属于巨核细胞系，在哺乳动物的骨髓中成熟，最后产生供循环使用的血小板。巨核细胞的成熟受到严格的控制，以控制生物体中循环中的血小板数量。在一个患有遗传性常染色体显性显性血小板减少症的家庭中，发现了Mastl激酶的单点突变。这一观察结果为这种新的激酶参与巨核细胞生成过程提供了证据。这项研究的具体目的是：1)确定巨核细胞在成熟过程中Mast1蛋白的表达模式、激酶活性和修饰；2)确定Mast1在造血模型系统中的作用；3)确定Mast1激酶底物在巨核细胞发育中的作用。尽管这些特定的目标代表着一个雄心勃勃的目标，但各种实验方法和途径将有助于拓展约翰逊博士的科学经验，并产生关于终末巨核细胞分化过程的重要数据，这可能导致治疗诱发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.