Mechanisms of Macrophage Activation

巨噬细胞激活机制

• 批准号: 7237249
• 负责人: THOMAS A. HAMILTON
• 金额: $ 28.09万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237249
• 关键词: Mechanisms; Macrophage; Activation

DESCRIPTION (provided by applicant): The contribution of mononuclear phagocytes in host response to cancer is determined in large part through the pattern of gene expression induced in response to stimuli encountered in the tumor microenvironment. Control of macrophage gene expression in response to prototypic pro-inflammatory (IFNgamma and LPS) or anti-inflammatory agents (IL-10 and TGFbeta) results from the integration of multiple intracellular signals that operate at both transcriptional and post-transcriptional levels. Current knowledge of post-transcriptional regulation of specific mRNA stability is limited. AU rich sequence elements (AREs) in the 3' untranslated regions (UTRs) of many cytokine and chemokine mRNAs in concert with ARE-specific RNA binding proteins lead to rapid mRNA decay. We and others have shown that pro-inflammatory or anti-inflammatory stimuli can stabilize or destabilize, respectively, selected chemokine mRNAs particularly KC (mouse CXCL1). These findings lead to the general hypothesis that post-transcriptional control of transiently expressed inflammatory genes involves the induced stabilization of unstable mRNAs through a process that operates in sequence specific fashion. Anti-inflammatory agents act by antagonizing this response. At present multiple features of this model remain undefined. These include (a) the sequence determinants for stimulus-dependent response, (b) how signaling pathways initiated by stabilizing and/or destabilizing agents are integrated and coupled with control of mRNA stability, (c) which steps in mRNA decay are altered by stabilizing or destabilizing stimuli and (d) how ARE-binding proteins couple signaling events to effector mechanisms responsible for the changes in mRNA decay. We now propose to address these issues as a further test of the hypothesis by performance of the following specific experimental aims. 1. Evaluate the sequence basis for ARE-dependent, stimulus-mediated control of mRNA stability. 2. Evaluate signaling pathways involved in the control of mRNA stability by LPS, IL-10 and TGFbeta. 3. Identify the mRNA decay mechanisms that are subject to stimulus-dependent modulation. 4. Determine the role of known ARE/RNA binding proteins in LPS-induced stabilization and IL-10 or TGFbeta-mediated destabilization

描述（由申请人提供）：单核吞噬细胞在宿主对癌症反应中的贡献在很大程度上是通过响应于肿瘤微环境中遇到的刺激的基因表达模式来确定的。控制巨噬细胞基因表达对原型促炎（IFNGAMMA和LPS）或抗炎剂（IL-10和TGFBETA）的反应，这是由于多个在转录和文字后水平上都在转录和文字后水平上作用的多个细胞内信号所致。当前对特定mRNA稳定性转录后调控的了解是有限的。许多细胞因子和趋化因子mRNA的3'未翻译区域（UTRS）中的富集序列元素（ARE）与特异性的RNA结合蛋白一致，导致mRNA衰减迅速。我们和其他人表明，促炎或抗炎刺激可以分别稳定或破坏稳定的趋势，尤其是KC（小鼠CXCL1）。这些发现导致了一个普遍的假设，即对瞬时表达的炎症基因的转录后控制涉及通过以序列特定方式运行的过程诱导不稳定mRNA的稳定。抗炎剂通过对抗这种反应来起作用。目前，该模型的多个功能仍然不确定。这些包括（a）依赖刺激的响应的序列决定因素，（b）如何通过稳定和/或破坏稳定剂引发的信号通路被整合并与控制mRNA稳定性的控制，（c）在mRNA衰减中的步骤通过稳定或破坏刺激的刺激和d构成prot的protiN的机制来改变mRNA衰减中的几个步骤。现在，我们建议解决这些问题，以进一步检验以下特定实验目标的性能。 1。评估依赖性刺激介导的mRNA稳定性的序列基础。 2。评估LPS，IL-10和TGFBETA控制mRNA稳定性涉及的信号通路。 3。确定受刺激依赖性调制的mRNA衰变机制。 4。确定已知的IS/RNA结合蛋白在LPS诱导的稳定和IL-10或TGFBETA介导的不稳定的作用