Regulation of Chemokine Expression In Vivo

体内趋化因子表达的调节

• 批准号: 6640235
• 负责人: THOMAS A. HAMILTON
• 金额: $ 33.3万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640235
• 关键词: T lymphocyte; chemokine; gene expression; genetically modified animals; inflammation; laboratory mouse; protein biosynthesis; skin hypersensitivity; surgical wound; wound healing

DESCRIPTION (provided by the applicant): Inflammation following tissue injury is an essential process that protects the organism against challenge by environmental pathogens and orchestrates the restoration of tissue architecture and homeostasis. A major aspect of this activity is dependent upon the sequential infiltration of inflammatory neutrophils and monocytes that is regulated, in part, by the production of chemoattractant cytokines or chemokines. Studies conducted in cultured cell lines have demonstrated that many cell types are capable of producing chemokines in response to a broad spectrum of agents. Our laboratory and others have demonstrated that chemokine expression is regulated through cell type- and stimulus-specific alterations in transcription and mRNA stability that depend upon specific nucleotide regulatory sequences in DNA and mRNA present in individual chemokine genes. Recent findings from our laboratory show that chemokine expression in vivo occurs in a complex multiphase pattern that is likely to involve the participation of distinct cell types and stimuli in a temporally ordered fashion. We cannot, however, accurately predict which individual stimuli, cell types, and mechanisms are responsible for the pattern of chemokine gene expression seen in any given inflammatory setting. The overall goal of this proposal, therefore, is to determine how the regulatory mechanisms identified from our cell culture models translate into the complex pattern of cell type- and stimulus-specific chemokine gene expression observed in vivo. This will be accomplished with two experimental objectives. 1. We will use mouse models of surgical injury or contact hypersensitivity in the skin to determine (a) the primary responding cell populations in each phase of response and (b) the pro-inflammatory and/or anti-inflammatory mediators responsible for regulating expression of KC and MIP-2 chemokine genes. 2. We will use transgenic mice expressing reporter transgenes containing wild type or mutant versions of defined regulatory sequences to determine their importance in controlling cell type- and stimulus-specific chemokine gene transcription and mRNA stability in vivo.

描述（由申请人提供）：组织损伤后的炎症是一个必不可少的过程，它可以保护有机体免受环境病原体的挑战，并策划了组织结构和稳态的恢复。该活性的一个主要方面取决于炎性嗜中性粒细胞和单核细胞的顺序浸润，部分地通过趋化剂细胞因子或趋化因子的产生来调节。在培养的细胞系中进行的研究表明，许多细胞类型能够响应广泛的药物而产生趋化因子。我们的实验室和其他实验室表明，趋化因子的表达是通过转录和mRNA稳定性的细胞类型和刺激特异性改变来调节的，这些细胞类型和mRNA稳定性依赖于单个趋化因子基因中存在的DNA和mRNA中特定的核苷酸调节序列。我们实验室的最新发现表明，体内趋化因子表达以复杂的多相模式发生，该模式可能涉及以时间顺序的方式参与不同的细胞类型和刺激。但是，我们不能准确预测哪些单独的刺激，细胞类型和机制是导致在任何给定炎症环境中看到的趋化因子基因表达的模式。因此，该提案的总体目标是确定从我们的细胞培养模型中鉴定出的调​​节机制如何转化为在体内观察到的细胞类型和刺激特异性趋化因子基因表达的复杂模式。这将通过两个实验目标来实现。 1。我们将使用皮肤外科损伤的小鼠模型或接触性超敏反应来确定（a）在每个反应的每个阶段中的主要反应细胞种群，以及（b）促炎和/或抗炎介质负责调节KC和MIP-2趋化因子基因的表达。 2。我们将使用表达含有野生型或突变版本的定义调节序列的转基因的转基因小鼠来确定它们在控制细胞类型和刺激特异性趋化因子基因转录和体内mRNA稳定性方面的重要性。