Mechanisms of Synergistic Regulation of Stem/Progenitors

描述（由申请人提供）：造血由相互作用的细胞因子调节，这些细胞因子作用于造血干细胞（HSC）和骨髓祖细胞（MPC）的增殖以及HSC的自我更新。我们确定了新的选择性作用，在体外和体内的IL-20的多能骨髓祖细胞（CFU-GEMM）的增殖与SCF组合使用时，并有初步的数据显示IL-20增强竞争性HSC在体内。我们认为，协同相互作用是至关重要的正常维护和生产的血细胞，并假设，IL-20，单独或与SCF，也许其他细胞因子的组合，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控和细胞周期检查点对HSC增殖和自我更新的正确调控至关重要，并假设，基于我们对SCF调控细胞周期不对称性的研究，以及对微管检查点的p21 cip 1/waf 1监测，有丝分裂纺锤体组装检查点（MSAC）密切参与HSC的正常增殖和自我更新。我们认为p21 cip 1/waf 1对HSC的作用至少部分是通过MSAC介导的。我们还推测IL-20联合SCF对MPC和HSC的作用部分通过p21 cip 1/waf 1和MSAC介导。我们的长期目标是确定调节HSC增殖和自我更新的细胞因子效应，以获得临床益处。为了实现这些目标，我们提出了以下目标：1。评价IL-20和SCF单独或联合对HSC和MPC增殖以及对HSC自我更新的影响。2.确定IL-20单独和与其他细胞因子联合对HSC细胞增殖和/或自我更新的作用机制，以及p21 cip 1/waf 1、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.