Mechanisms of Synergistic Regulation of Stem/Progenitors

描述（由申请人提供）：造血是由相互作用的细胞因子调节的，这些细胞因子作用于造血干细胞（HSC）和髓系祖细胞（MPC）的增殖以及HSC的自我更新。我们在体外和体内发现了IL-20在与SCF联合使用时对多潜能髓系祖细胞（CFU-GEMM）增殖的新的选择性作用，并有初步数据显示IL-20在体内增强竞争性HSC。我们认为，协同作用对血细胞的正常维持和产生至关重要，并假设IL-20单独或与SCF以及其他细胞因子联合，将增强HSC的增殖，并可能参与调节HSC的自我更新。我们认为细胞周期调节和细胞周期检查点对于正确调节HSC的增殖和自我更新至关重要，并基于我们对SCF对细胞周期不对称的调节和p21cip1/waf1对微管检查点的监测的研究，假设有丝分裂纺锤体组装检查点（MSAC）密切参与了HSC的正常增殖和自我更新，并且是必要的。我们认为p21cip1/waf1对HSC的影响至少部分是通过MSAC介导的。我们还假设IL-20联合SCF对MPC和HSC的影响部分是通过p21cip1/waf1和MSAC介导的。我们的长期目标是确定细胞因子的作用，调节增殖和自我更新的HSC临床效益。为实现这些目标，我们提出以下目标：评估IL-20和SCF单独或联合对HSC和MPC增殖以及HSC自我更新的影响。2. 确定IL-20单独或联合其他细胞因子对HSC细胞增殖和/或自我更新的作用机制，以及p21cip1/waf1、StatS、Wnt-GSK-3通路和SOCS在介导这些作用中的潜在作用。3. 阐明MSAC在HSC和MPC增殖以及HSC自我更新中的作用，并将这些作用与细胞因子对这些功能的作用联系起来。

DESCRIPTION (provided by applicant): Hematopoiesis is regulated by interacting cytokines that act on proliferation of hematopoietic stem cells (HSC) and myeloid progenitor cells (MPC) and on self-renewal of HSC. We identified novel selective actions in vitro and in vivo of IL-20 on proliferation of multipotential myeloid progenitor cells (CFU-GEMM) when used in combination with SCF, and have preliminary data showing IL-20 enhancement of competitive HSC in vivo. We believe that synergistic interactions are critical for normal maintenance and production of blood cells, and hypothesize that IL-20, alone or in combination with SCF, and perhaps other cytokines, will enhance proliferation of HSC and may be involved in the regulation of self-renewal of HSC. We consider cell cycle regulation and cell cycle checkpoints critical for correct regulation of proliferation and self-renewal of HSC, and hypothesize, based on our studies on SCF regulation of cell cycle asymmetry, and on p21cip1/waf1 monitoring of microtubule checkpoints, that the mitotic spindle assembly checkpoint (MSAC) is intimately involved in, and necessary for normal proliferation and self-renewal of HSC. We believe that the effects of p21cip1/waf1 on HSC, are at least in part mediated through the MSAC. We also hypothesize that the effects of IL-20, in combination with SCF on MPC and on HSC are mediated in part through p21cip1/waf1 and the MSAC. Our long term goals are to define cytokine effects that modulate proliferation and self-renewal of HSC for clinical benefit. Towards these goals we propose the following aims: 1. Evaluate effects of IL-20 and SCF, alone and in combination, on proliferation of HSC and MPC, and on self-renewal of HSC. 2. Determine mechanisms of action of IL-20 alone and in combination with other cytokines on cell proliferation and/or self-renewal of HSC and the potential roles of p21cip1/waf1, StatS, Wnt-GSK-3 pathway and SOCS in mediating these actions. 3. Elucidate the role of MSAC in proliferation of HSC and MPC, and in self-renewal of HSC, and link these effects to cytokine actions on these functions.