Defining a Niche: How a Blood Stem Cell Niche Develops

描述（由申请人提供）：严格调节控制血细胞的内部和外部因素对于维持组织稳态和预防骨髓增生性疾病和白血病很重要。特别是，造血干细胞及其支持微环境是造血组织稳态的根本。成人造血干细胞生态位发育和维持的机制在很大程度上是未知的。利用斑马鱼的遗传模型，我建议鉴定和表征对成年造血干细胞生态位的发育和维持重要的基因。我将使用荧光延时共聚焦显微镜来动态监测斑马鱼生态位的发展。从这个分析的信息将是基础的向前遗传筛选，以确定必要的成人造血生态位形成的基因。鉴定的基因将包括在生态位内成人造血细胞的生物迁移、扩张和存活所需的基因。此外，该研究的结果可以揭示疾病状态中被错误调节的潜在途径。在此筛选中获得的信息将有助于开发针对血液恶性肿瘤和免疫缺陷的新疗法。

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.