Homing Determinants in Hemopoietic Stem/Progenitor Cells

造血干细胞/祖细胞中的归巢决定因素

• 批准号: 6845255
• 负责人: THALIA STAMATOYANNOPOULOS
• 金额: $ 34.11万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845255
• 关键词: CD antigens; G protein; NOD mouse; SCID mouse; biological signal transduction; bone marrow; bone marrow transplantation; cell cell interaction; cell differentiation; cell growth regulation; cell migration; cell proliferation; chemotaxis; clinical research; flow cytometry; gene expression; gene mutation; genetic models; hematopoietic stem cells; human tissue; laboratory mouse; protein structure function; tissue /cell culture; vascular cell adhesion molecule; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): Intravenously administered hemopoietic cells colonize the BM extravascular spaces that support their proliferative expansion/differentiation. This phase of hemopoietic engraftment is preceded by a phase of initial capture of the cells within BM sinusoids followed by adhesion/migration steps leading to their firm anchoring within BM. The molecular pathways responsible for this initial phase are distinct from the ones dictating their engraftment, however, they are poorly understood, and thought to involve members of the integrin family and chemokines. In preliminary data we have shown that the VLA-4/VCAM-1 pathway has a dominant role in the initial phases of homing, but a multi-component participation in adhesion/migration steps is likely. The identity of cooperating molecules and their functional contribution to specific phases in homing remain to be delineated. In this application we will expand our observations using a multi-parameter approach incorporating genetic mouse models with conditional ablation of specific target molecules (VCAM-1) or using mice harboring hemopoietic cells with altered Gi protein signaling. The participation of VCAM-1 expressed by hemopoietic cells - a novel finding - or by hemopoietic stroma/endothelial cells in the initial stages of homing within BM or liver or spleen and in the maintenance of the hemopoietic graft within these tissues, will be studied in SA#1 using genetic models with conditional VCAM-1 ablation. The contribution of Gi protein signaling pathway in homing and in the retention of cells within BM niches will be the focus of SA#2. Finally, in SA#3, we will extend our new observations that BM derived cells residing in muscle retain hemopoietic reconstituting activity and we will test the kinetics, the turnover post-transplantation, and their potential expansion through drug-induced (CID) proliferation. As BM-derived cells, both CD45+ or CD45-, have become an important paradigm of postnatal stem cell plasticity, these studies will provide a glimpse of a previously unappreciated tissue distribution and survival of BM derived cells, a new facet in BM physiology.

描述（由申请人提供）：静脉内施用的血压细胞定居BM血管外空间，以支持其增殖性扩张/分化。在本性植入的这一阶段之前是对BM正弦体内细胞的初始捕获阶段，然后是粘附/迁移步骤，导致其公司锚定在BM内。负责此初始阶段的分子途径与决定其植入的分子途径不同，但是，它们的理解很少，并且被认为与整合素家族和趋化因子的成员有关。在初步数据中，我们已经表明，VLA-4/VCAM-1途径在归巢的初始阶段具有主要作用，但是多组分参与粘附/迁移步骤可能。合作分子的身份及其对归居特定阶段的功能贡献仍有待描绘。在此应用中，我们将使用多参数方法扩展观察结果，该方法结合了特定靶分子（VCAM-1）的遗传小鼠模型，或使用具有改变GI蛋白信号传导的垂直细胞的小鼠。血压细胞表达的VCAM -1的参与 - 一种新发现 - 或由血压基质/内皮细胞在BM，肝脏或脾内的归巢的初始阶段，以及在这些组织中的血压移植物中的维持中，将在SA＃1中使用具有条件VCAM -1 Ablation的遗传模型进行研究。胃肠道蛋白信号通路在归巢中和在BM壁ches中保留细胞中的贡献将是SA＃2的重点。最后，在SA＃3中，我们将扩展我们的新观察结果，即BM衍生在肌肉中的细胞保留了血压重建活性，我们将测试动力学，转移后转移后的周转及其通过药物诱导的（CID）增殖的潜在扩张。由于CD45+或CD45-的BM衍生细胞已成为产后干细胞可塑性的重要范式，这些研究将瞥见BM生理学中的新面BM衍生细胞的先前未批准的组织分布和存活。