Defining a Niche: How a Blood Stem Cell Niche Develops

描述（由申请人提供）：控制血细胞的内部和外部因素的严格调节在维持组织稳态和预防骨髓增生性疾病和白血病方面很重要。特别是，造血干细胞及其支持性微环境是造血组织稳态的根源。成体造血干细胞小生境的发育和维持的机制在很大程度上是未知的。使用的遗传模型斑马鱼（斑马鱼），我建议识别和表征基因的发展和维护的成人造血干细胞生态位的重要性。我将使用荧光延时共聚焦显微镜来动态监测斑马鱼的生态位的发展。从这个分析的信息将是一个正向遗传筛选的基础，以确定成人造血生态位形成所需的基因。所鉴定的基因将包括在小生境内成体造血细胞的生物迁移、扩增和存活所需的那些基因。此外，拟议研究的结果可以揭示疾病状态中潜在的失调途径。在这个屏幕上获得的信息将是有用的，在开发新的治疗血液恶性肿瘤和免疫缺陷。

DESCRIPTION (provided by applicant): Tight regulation of internal and external factors controlling blood cells is important in maintaining tissue homeostasis and preventing myeloproliferative disorders and leukemias. In particular, hematopoietic stem cells and their supportive microenvironment are at the root of hematopoietic tissue homeostasis. The mechanisms underlying the development and maintenance of the adult hematopoietic stem cell niche are largely unknown. Using the genetic model Danio rerio (zebrafish), I propose to identify and characterize genes important to the development and maintenance of the adult hematopoietic stem cell niche. I will use fluorescent time-lapse confocal microscopy to dynamically monitor the development of the niche in zebrafish. The information from this analysis will be the basis for a forward genetic screen to identify genes necessary for adult hematopoietic niche formation. Genes identified will include those required for the biological migration, expansion, and survival of adult hematopoietic cells within the niche. Additionally, the results from the proposed study can reveal potential pathways misregulated in disease states. Information gained in this screen will be useful in developing novel therapies for hematologic malignancies and immune deficiencies.