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种时空波发展，产生适合胚胎需要的专门细胞类型。从胚胎中产生的细胞，成体造血干细胞（HSC）形成。成体HSC反过来继续自我补充并产生后代，这些后代在成体中填充大多数血液谱系。理解控制和响应这些转变的过程和分子是我们操纵正常和异常造血的能力的基础，例如干细胞治疗。 在这个建议中，我们将使用MII基因的小鼠功能丧失模型来探测血液发育的早期胚胎阶段以及成年人的稳态造血。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。我们已经表明，MII是必需的发展确定的造血谱系。在这里，我们试图提供详细的信息，发展动态和机制，MII参与造血谱系的发展。具体而言，我们将1）通过将来自MII突变胚胎的造血组织移植到合适的受体中来鉴定胚胎HSC特化和扩增期间的MLL依赖性过程，2）利用体外系统来鉴定和操纵对促进血液发育重要的MLL靶基因，和3）在成年稳态造血群体中使用MII基因座的条件失活来鉴定和研究谱系定型期间和之后的MII依赖性过程。这项提案的目标是揭示重要的调控过程和网络的造血系统的发展和维护使用的基因是至关重要的这些过程。 该奖项将为主要研究者Patricia Ernst博士和赞助商Stanley Korsmeyer博士提供一段时间的指导。Dr. Ernst已建立了在申办方实验室执行该提案的系统。Korsmyeyer博士是肿瘤发生领域的世界领导者，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着良好的记录

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