MOLECULAR PATHWAYS OF LEUKOCYTE HOMING TO BONE MARROW

造血干细胞(HSC)从血液到家的能力 骨髓中特殊的微环境是临床的基础 骨髓移植的成功，这是越来越多的 对多种疾病的治疗很重要。尽管有 骨髓移植的临床重要性，分子生物学 负责向骨髓输送造血干细胞的机制 人们对此了解甚少。了解这些机制将使 HSC归巢受体表达和/或活性的可能操纵， 并可能提高骨髓移植的疗效 各种临床环境。我们假设HSC至少使用了一些 具有与正常、成熟的相同的途径和黏附分子 白细胞在与内皮细胞相互作用过程中的使用 进入组织的通道。这项提案详细介绍了确定 选择素在造血干细胞运输中的作用，特别是在骨髓归巢中的作用。 选择素是一个由三个碳水化合物结合的黏附分子组成的家族 有充分的证据表明，在正常的监管中发挥关键作用 白细胞运输，特别是在白细胞的初始相互作用中 有内皮细胞。在第一个具体目标中，我们将评估 选择素在骨髓间充质干细胞交通中的作用 适当的选择素基因敲除小鼠的骨髓细胞可以重建 受到致命辐射的野生型窝产仔；反之，是否 正常骨髓细胞移植可以致命地重建 照射后的选择素基因敲除小鼠。重建将由Long来评估 照射小鼠的存活期(大于100天)，并将 经标记供者的多血统重建分析证实 骨髓细胞。在具体目标2中，我们将确定是否正常 浆细胞，像HSC一样，也表现出强烈的归巢倾向 骨髓，也使用选择素在其迁移到 骨髓，以及这些细胞还使用哪些其他黏附途径 细胞。这些实验将确定选择素在HSC和HSC中的作用 浆细胞运输到骨髓，并将开始定义在 分子水平白细胞归巢至骨髓的途径。

The ability of hematopoietic stem cells (HSC) to home from the blood into specialized microenvironments in the bone marrow underlies the clinical success of bone marrow transplantation, which is becoming increasingly important for the treatment of a variety of diseases. In spite of the clinical importance of bone marrow transplantation, the molecular mechanisms which are responsible for HSC traffic to the bone marrow are poorly understood. Understanding these mechanisms would make possible manipulation of HSC homing receptor expression and/or activity, and may improve the efficacy of bone marrow transplantation in a variety of clinical settings. We hypothesize that HSC use at least some of the same pathways and adhesion molecules as normal, mature leukocytes use during their interaction with endothelium and subsequent passage into tissues. This proposal details experiments to determine the role of selectins in HSC traffic, especially homing to bone marrow. Selectins are a family of three carbohydrate-binding adhesion molecules well documented to play a critical role in the regulation of normal leukocyte traffic, specifically in the initial interactions of leukocytes with endothelium. In the first specific aim, we will evaluate the role of the selectins in HSC traffic by testing whether transplantation of bone marrow cells from appropriate selectin knockout mice can reconstitute lethally irradiated wild type littermates; and conversely, whether transplantation of normal bone marrow cells can reconstitute lethally irradiated selectin knockout mice. Reconstitution will be assess by long term (greater than 100 days) survival of the irradiated mice, and will be confirmed by analysis of multilineage reconstitution from marked donor bone marrow cells. In specific aim #2, we will determine whether normal plasma cells, which like HSC also exhibit a strong tendency to home into bone marrow, also use selectins in the course of their migration into bone marrow, and which other adhesion pathways are used by these cells. These experiments will identify the role selectins play in HSC and plasma cell traffic to bone marrow, and will begin to define at the molecular level the pathways of leukocyte homing to bone marrow.