MII Regulation of Hematopoiesis

描述(由申请人提供)： 脊椎动物的血液形成系统在胚胎发生期间以几个时空波的形式发展，产生适合胚胎需要的特殊细胞类型。由胚胎中产生的细胞形成成人造血干细胞(HSCs)。反过来，成年的造血干细胞继续自我补充，并产生子代，这些后代充斥着成年的大多数血统。了解控制和响应这些转变的过程和分子，是我们为了干细胞治疗等目的而操纵正常和异常造血的能力的基础。 在这项提议中，我们将使用MII基因中的小鼠功能丧失模型来探索血液发育的早期胚胎阶段以及成人的稳定状态造血。MII基因是一种原癌基因，通过修饰染色质参与HOX和其他靶基因的发育调控。我们已经证明，MII对于最终的造血系的发展是必需的。在这里，我们试图提供有关MII参与造血系发育的发育动力学和机制的详细信息。具体地说，我们将1)通过将MII突变胚胎的造血组织移植到适当的受体来识别胚胎HSC指定和扩增过程中的MLL依赖过程，2)开发体外系统来识别和操纵对促进血液发育重要的MLL靶基因，3)利用成年稳态造血群体中MII基因的条件失活来识别和研究MII依赖的过程在血统承诺期间和之后。这项提议的目标是利用一种已知对这些过程至关重要的基因，揭示在造血系统的发展和维护中的重要调控过程和网络。 该奖项将为首席研究员Patricia Ernst博士和赞助商Stanley Korsmeyer博士提供一段时间的指导。恩斯特博士已经在赞助商的实验室建立了实施这项提议的系统。Korsmyeyer博士是肿瘤发生领域的世界领导者，他确立了细胞凋亡在这一过程中的重要性。Korsmeyer博士在培训和培养独立调查人员方面有很好的记录

DESCRIPTION (provided by applicant): The blood forming system of vertebrates develops during embryogenesis in several spatio-temporal waves that produce specialized cell types suited for the needs of the embryo. From cells generated in the embryo, adult hematopoietic stem cells (HSCs) form. Adult HSCs, in turn, continue to replenish themselves and yield progeny that populate most blood lineages in the adult. Understanding the processes and molecules controlling and responding to these transitions underlies our ability to manipulate normal and aberrant hematopoiesis for purposes such as stem cell therapy. In this proposal, we will use a murine loss-of-function model in the MII gene to probe early embryonic stages of blood development as well as steady-state hematopoiesis in the adult. The MII gene is a proto-oncogene that participates in the developmental regulation of Hox and other target genes by modifying chromatin. We have shown that MII is required for the development of definitive hematopoietic lineages. Here, we seek to provide detailed information regarding the developmental dynamics and mechanism by which MII participates in the development of hematopoietic lineages. Specifically, we will 1) identify MLL-dependent processes during embryonic HSC specification and expansion by transplanting hematopoietic tissues from MII mutant embryos into appropriate recipients, 2) exploit an in vitro system to identify and manipulate MLL target genes that are important for promoting blood development, and 3) use conditional inactivation of the MII locus in adult steady-state hematopoietic populations to identify and study MII-dependent processes during and beyond lineage commitment. The goal of this proposal is to uncover important regulatory processes and networks in the development and maintenance of the hematopoetic system using a gene known to be critical for these processes. This award will provide a period of mentorship for Dr. Patricia Ernst, the principal investigator, with Dr. Stanley Korsmeyer, the sponsor. Dr. Ernst has established the systems to carry out this proposal in the sponsor's laboratory. Dr. Korsmyeyer is a world leader in the field of oncogenesis establishing the importance of apoptosis in this process. Dr. Korsmeyer has a strong record of training and fostering independent investigators