CHEMOKINE REGULATION IN IMMUNE COMPLEX RENAL DISEASE

免疫复合物肾病中的趋化因子调节

• 批准号: 6042634
• 负责人: BRAD H ROVIN
• 金额: $ 21.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6042634
• 关键词: cell cell interaction; clinical research; cytokine; gene expression; genetic polymorphism; genetic regulation; human subject; human tissue; immune complex; inflammation; kidney cell; kidney disorder; leukocytes; nucleic acid sequence; regulatory gene; reporter genes; systemic lupus erythematosus; tissue /cell culture

Compelling evidence indicates that chemokines play a key role in the development of renal inflammation. The regulation of chemokine expression in human renal disease is poorly understood. This investigation will examine molecular, cellular, and genetic aspects of chemokine regulation in the context of a clinically relevant mechanism of immune injury, immune complex (IC)-mediated renal inflammation. In Aim 1 the hypothesis that IC-induced chemokine expression in the kidney is mediated by FCgamma- receptor III-bearing lymphocytes that have been activated by IC will be tested. A cell culture model of pathogenic IC interaction with leukocytes and renal parenchymal cells will be used for this evaluation. In vivo correlates to support the model will be sought in a patient population with systemic lupus erythematosus (SLE) nephritis, a classical IC-dependent renal lesion. Because polymorphisms of Fc receptors have been described that alter Fc receptor function, it is conceivable that Fc-receptor mediated chemokine expression is influenced by Fc receptor phenotype. Therefore, the effect of Fc receptor polymorphisms on IC-induced leukocyte chemokine production will be assessed. In Aim 2, the theme of genetic regulation of chemokine expression will be expanded by testing the hypothesis that polymorphisms in the regulatory regions of chemokine genes affect the level of chemokine production, and consequently the degree of tissue inflammation in response to IC or pro- inflammatory cytokines. Genomic DNA from a normal population will be sequenced to identify polymorphisms in the regulatory elements of chemokine genes. Polymorphic variants of these regulatory regions will be inserted into reporter vectors for functional evaluation. The prevalence of functional regulatory region polymorphisms will be assessed in the SLE nephritis patient population, and correlated to severity of renal injury. These studies are expected to offer novel insights into the molecular and cellular mechanisms that initiate inflammation and determine the severity of inflammation in IC renal disease. This information will likely suggest new directions for interventions to control renal inflammation.

令人信服的证据表明，趋化因子在肾脏炎症的发展中起着关键作用。 趋化因子在人类肾脏疾病中的表达调控还知之甚少。本研究将在免疫损伤、免疫复合物（IC）介导的肾脏炎症的临床相关机制的背景下，研究趋化因子调节的分子、细胞和遗传方面。 在目的1中，将检验以下假设：IC诱导的趋化因子在肾脏中的表达是由IC激活的携带Fc γ受体III的淋巴细胞介导的。 本评价将使用致病性IC与白细胞和肾实质细胞相互作用的细胞培养模型。 将在患有系统性红斑狼疮（SLE）肾炎（一种经典的IC依赖性肾脏病变）的患者人群中寻找支持该模型的体内相关性。 由于Fc受体的多态性已被描述为改变Fc受体功能，因此可以想象Fc受体介导的趋化因子表达受Fc受体表型的影响。 因此，将评估Fc受体多态性对IC诱导的白细胞趋化因子产生的影响。 在目的2中，趋化因子表达的遗传调节的主题将通过测试以下假设来扩展：趋化因子基因的调节区域中的多态性影响趋化因子产生的水平，并且因此影响响应于IC或促炎细胞因子的组织炎症的程度。 将对正常人群的基因组DNA进行测序，以鉴定趋化因子基因调控元件的多态性。 将这些调控区的多态性变体插入报告载体中进行功能评价。 将在SLE肾炎患者人群中评估功能调节区多态性的患病率，并将其与肾损伤的严重程度相关联。这些研究有望为IC肾病中引发炎症并确定炎症严重程度的分子和细胞机制提供新的见解。 这些信息可能会为控制肾脏炎症的干预措施提供新的方向。