BIOLOGICAL PROPERTIES AND REGULATION OF STEM CELLS

描述：（研究者摘要）细胞粘附受体-配体介导 造血细胞和它们的环境之间的相互作用被认为是 负责其具体的本地化和维护， 解剖部位以及它们随后的生长、分化和 生存此外，这些专门的相互作用允许移民， 特定细胞类型（即，成熟细胞的出口），并促进 IV输注的供体造血细胞在 移植剖析这些分子的复杂性， 由于几种粘附分子的功能， 与大量其他粘附伙伴一起， 通过几种生长因子受体及其配体以相互作用的方式 存在于造血细胞和/或其环境中。然而，重要的是 已经在体外，特别是在体内从患有 几个基因的基因切除。通过各种办法的结合， α 4/1整联蛋白已成为调节 造血然而，其对增殖、维持、 造血细胞的分化和迁移尚未被描述。 在具体目标#1中，我们将研究α 4/1整联蛋白在 胎儿和成人造血。具体来说，α 4整合素消融的影响 关于增殖/分化/维持/贩运 红细胞/巨核细胞或所有造血谱系将使用a） 谱系特异性或B）造血特异性cre介导的a4切除 整联蛋白条件性a4消融的影响，无论是在胎儿期还是成人期 将使用两种方法研究生命：a）我们的a4“floxed”的繁殖 动物是携带cre诱导型启动子的动物，和B）移植 体外从成人骨髓或胎儿骨髓中切除A4“融合”细胞 肝脏，以确定归巢潜力和植入的持久性。在特定 目的#2我们将在一种新的动物模型中研究细胞增殖的影响 本身的动员，以及动员细胞的动力学和周转 与天然生长因子相比，通过使用促有丝分裂药物。在 具体目标#3，我们将尝试通过系统的方法和使用 基因缺陷小鼠来揭示碳水化合物-蛋白质相互作用 导致动员;审查是否治疗后释放的 趋化因子或细胞-基质相互作用的破坏是使用 缺乏趋化因子或选择素的小鼠;并研究其结构 赋予碳水化合物的特异性， 动员。

DESCRIPTION: (Investigator's abstract) Cytoadhesive receptor-ligand mediated interactions between hemopoietic cells and their environment are thought to be responsible for their specific localization and maintenance in discrete anatomic sites as well as for their subsequent growth, differentiation, and survival. Furthermore, these specialized interactions allow emigration of specific cells types (i.e., egress of mature cells) and facilitate the settlement and colonization of IV infused donor hemopoietic cells in transplantation. Dissection of the molecular complexities that underlie these interactions in vivo has been difficult, as several adhesion molecules function in concert with a large number of other adhesion partners, and are influenced in a reciprocal fashion by several growth factor receptors and their ligands present in hemopoietic cells and/or their environment. Nevertheless, important insights have been obtained in vitro and especially in vivo from mice with genetic ablations of several genes. Through a combination of approaches the a4/fl1 integrin has emerged as a major player in the regulation of hematopoiesis. However, its specific effects on proliferation, maintenance, differentiation and migration of hematopoietic cells have not been delineated. In Specific Aim #1, we will investigate the role of a4/fl1 integrins in fetal and adult hematopoiesis. Specifically, the impact of a4 integrin ablation on proliferation/differentiation/maintenance/trafficking on erythroid/megakaryocytic or all hemopoietic lineages will be studied using a) lineage specific or b) hemopoietic specific cre-mediated excision of a4 integrin. The impact of conditional a4 ablation, either during fetal or adult life will be studied using two approaches: a) breeding of our a4 "floxed" animals will animals carrying cre-inducible promoters and b) transplantation of in vitro cre-excised a4 "floxed" cells from adult bone marrow or from fetal liver to ascertain homing potential and durability of engraftment. In Specific Aim #2 we will examine in a novel animal model the impact of cell proliferation per se on mobilization, and the kinetics and turnover of cells mobilized through the use of a mitogenic drug as compared to natural growth factors. In Specific Aim #3, we will attempt through a systematic approach and the use of genetically deficient mice to unravel how carbohydrate-protein interactions lead to mobilization; to examine whether the post-treatment release of chemokines or the disruption of cell-stroma interactions are responsible using mice lacking chemokines or selectins; and to investigate the structural specificities that impart in carbohydrate compounds the ability to elicit mobilization.