Defining a Niche: How a Blood Stem Cell Niche Develops

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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.