MECHANISMS OF SYNERGISTIC REGULATION OF STEM/PROGENITORS

描述：(改编自申请者摘要)血细胞控制 生产涉及细胞因子-细胞相互作用，其中细胞因子 对造血干细胞有正反两种作用 祖细胞。增长因素，如钢铁系数(SLF)和 集落刺激因子(Csf)可协同作用。 效果。协同刺激可以被趋化因子等抑制 作为巨噬细胞炎症蛋白(MIP)-1α，干扰素诱导 蛋白(IP)-10、IL-8和血小板因子(PF)4；趋化因子可起作用 共同抑制经济增长。这是我们的假设 在细胞内存在不同的和重叠的通路来调节 多种细胞因子对细胞增殖的协同刺激作用 趋化因子的抑制发生在细胞内的生长部位 协同刺激事件的因素。我们的目标是评估这些 使用因子依赖的髓系细胞系的途径，并进行验证 在可行的情况下，使用原代细胞。具体目标是：1)继续 Raf-1/MEK-1/MAP-Kinase信号转导通路在细胞周期调控中的作用 黄曲霉毒素诱导的细胞增殖协同刺激的介体 SLF加脑脊液和c-AMP依赖的蛋白激酶A的抑制作用 活性对Raf-1激活的负效应部位 MIP-1α和IP-10表达于MEKK1/Sek1/SAP-Kinase和MKK3/Hog/MAP-APK2- 作为协同诱导细胞刺激的可能部位 增殖，以及趋化因子对其的负调控。测定 协同诱导即刻上调的作用 C-fos、JunB、c-egR和c-myc等反应基因可能的作用位点 趋化因子的负性调节。尽可能地评估以上几点 协同诱导抑制细胞增殖的部位 通过以下任何两种低浓度的组合 趋化因子：MIP-1α、IP-10、IL-8或PF4。2)为以下对象建立角色 细胞周期蛋白依赖性激酶抑制因子p21CIP-1和p27KIP-1在 协同诱导刺激细胞增殖及测定 如果这是趋化因子抑制细胞生长的部位。3)评估 真核细胞起始因子4E(EIF4E)在人类免疫缺陷中的作用 细胞中蛋白质合成水平协同增强 系统性红斑狼疮和脑脊液刺激细胞增殖 这是通过MIP-1α、IP-10、IL-8和PF4实现的。4)评估以下项目的角色 蛋白酪氨酸磷酸酶SYP和PRP-1C协同诱导 趋化因子家族对细胞增殖的促进作用及其抑制作用 会员。

DESCRIPTION: (Adapted from Applicant's Abstract) Control of blood cell production involves cytokine-cell interactions in which cytokines manifest positive and negative effects on hematopoietic stem and progenitor cells. Growth factors such as steel factor (SLF) and a colony-stimulating factor (CSF) can act together to elicit synergistic effects. Synergistic stimulation can be suppressed by chemokines such as macrophage inflammatory protein (MIP)- 1alpha, interferon inducible protein (IP)-10, IL-8 and platelet factor (PF)4; chemokines can act together to synergistically suppress growth. It is our hypothesis that distinct and overlapping pathways exist within a cell to mediate synergistic stimulation of cell proliferation by multiple cytokines and suppression by chemokines is occurring at intracellular sites of growth factor synergistically stimulated events. Our goal is to evaluate these pathways using factor-dependent myeloid cell lines, with verification where feasible with primary cells. The specific aims are: 1) continue investigation of the role of the Raf-1/MEK-1/MAP-kinase pathway as a mediator of the synergistic stimulation of cell proliferation induced by SLF plus a CSF, and of the c-AMP-dependent protein kinase A inhibitory activity on Raf-1 activation as a site of the negative effects of MIP-1alpha and IP-10 on MEKK1/Sekl/SAP-kinase, and MKK3/Hog/MAP-APK2- kinase, as possible sites for synergistically-induced stimulation of cell proliferation, and its negative regulation by chemokines. Determine a role for the synergistically-induced up-regulation of immediate response genes such as c-fos, junB, c-egr and c-myc as possible sites of negative regulation by chemokines. Evaluate the above as possible sites for synergistically-induced suppression of cell proliferation by combinations of low concentrations of any two of the following chemokines: MIP-1alpha, IP-10, IL-8 or PF4. 2) Establish a role for the cyclin-dependent kinase inhibitors, p21CIP-1 and p27KIP-1 in synergistically-induced stimulation of cell proliferation and determine if this is a site of chemokine suppression of cell growth. 3) Evaluate a role for eukaryotic initiation factor 4E (eIF4E) in the greatly enhanced level of protein synthesis seen in cells synergistically stimulated to proliferate by SLF and a CSF and in the suppression of this by MIP-1alpha, IP-10, IL-8 and PF4. 4) Evaluate roles for the protein tyrosine phosphatases Syp and PRP-1C in synergistically-induced stimulation of cell proliferation and its suppression by chemokine family members.