BIOLOGICAL PROPERTIES AND REGULATION OF STEM CELLS

描述：(研究人员摘要)细胞黏附受体-配体介导的造血细胞与其环境之间的相互作用被认为是 负责其具体的本地化和分立维护 解剖部位以及它们随后的生长、分化和 生死存亡。此外，这些专门的互动允许移民 特定的细胞类型(即成熟细胞的出口)，并促进 静脉输注的供者造血细胞在小鼠体内的定居和定植 移植。对这些基础上的分子复杂性的剖析 体内的相互作用一直很困难，因为有几个黏附分子发挥作用 与大量其他粘连伙伴协同工作，并受到影响 通过几种生长因子受体及其配体相互作用 存在于造血细胞和/或其环境中。尽管如此，重要的是 已经在体外，特别是在体内从小鼠身上获得了见解 几个基因的基因消融。通过多种方法的组合， A4/&#64258；1整合素已成为调节 造血术。然而，它在扩散，维持， 造血细胞的分化和迁移尚未被描绘出来。 在特定的目标1中，我们将研究A4/&64258；1整合素在 胎儿和成人的造血。特别是，A4整合素消融的影响 On proliferation/differentiation/maintenance/trafficking On 红系/巨核系或所有造血系的研究将使用 谱系特异性或b)造血特异性cre介导的A4切除 整合素。条件A4消融术对胎儿和成人的影响 我们将用两种方法来研究生命：a)培育我们的A4“丛生” 动物将携带可诱导启动子的动物和b)移植 体外分离成人骨髓或胎儿骨髓中的A4细胞 以确定植入的归巢潜力和耐久性。具体而言 目的#2我们将在一个新的动物模型中检查细胞增殖的影响 本身对动员，以及动员的细胞的动力学和周转 通过使用促有丝分裂药物与自然生长因子进行比较。在……里面 具体目标#3，我们将尝试通过系统的方法和使用 基因缺陷小鼠揭开碳水化合物和蛋白质的相互作用 导致动员；检查治疗后释放的 趋化因子或细胞-间质相互作用的中断是使用 缺乏趋化因子或选择素的小鼠；并研究其结构 在碳水化合物中赋予的特异性能够诱导 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.