Transcriptional Regulation of Matrix Metalloproteinase-3

基质金属蛋白酶 3 的转录调控

• 批准号: 7077495
• 负责人: RUTH C BORGHAEI
• 金额: $ 2.88万
• 依托单位: PHILADELPHIA COLLEGE OF OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077495
• 关键词: chromatin immunoprecipitation; clinical research; gel mobility shift assay; gene expression; gene induction /repression; genetic polymorphism; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; genotype; human subject; immunoprecipitation; interleukin 1; interleukin 4; molecular site; periodontitis; posttranslational modifications; protein protein interaction; protein structure function; site directed mutagenesis; stromelysin; tissue /cell culture; transcription factor; transfection

DESCRIPTION: In periodontitis, levels of inflammatory cytokine IL-1 are high and correlate with disease severity, while levels of anti-inflammatory IL-4 are low or undetectable and decreasing levels of IL-4 correlate with increasing severity. IL-1 contributes to loss of attachment and alveolar bone destruction by increasing expression of matrix metalloproteinases. MMP-3 has broad substrate specificity and can activate other pro-MMP. It is found in increased levels in diseased sites, and levels are correlated with severity and progression. Previous studies identified the SIRE site (stromelysin IL-1 responsive element) as a repressor element involved in suppressing the IL-1 induction of MMP-3. Others also identified this site as a common 5T/6T polymorphism, with the 6T site being a more effective repressor element. Genotype at this site has been linked to tissue levels of MMP-3 and to susceptibility or severity of a number of diseases. In cardiovascular disease (a condition associated with periodontitis), homozygosity for the higher-expressing 5T allele is associated with myocardial infarction and aneurysm, while the lower-expressing 6T allele is associated with atherosclerosis. It is therefore clear that regulation of this gene must be tightly controlled to maintain correct tissue homeostasis, and that understanding these control mechanisms is important for a variety of pathologies. We recently found that proteins binding to the SIRE site include NF-kappaB p50 and p65 and ZBP-89. We also recently showed that IL-1 induction of MMP-3 is suppressed by IL-4 in human gingival fibroblasts isolated from patients with periodontitis. The Specific Aims of this application are to: 1) study the roles of transcription factors interacting with the polymorphic SIRE site in the MMP-3 promoter, and 2) determine the mechanism of suppression of MMP-3 expression by IL-4. In doing so, we hope to gain information about complex gene regulatory mechanisms involved in MMP-3 regulation, but also continue to contribute to the research environment at PCOM and to the training of its students in research in general, and molecular biology in particular.

描述：在牙周炎中，炎症细胞因子IL-1水平高且与疾病严重程度相关，而抗炎细胞因子IL-4水平低或检测不到，IL-4水平下降与疾病严重程度增加相关。IL-1通过增加基质金属蛋白酶的表达而导致骨附着丧失和牙槽骨破坏。MMP-3具有广泛的底物特异性，并能激活其他mmp前体。它在患病部位的水平升高，并且水平与严重程度和进展相关。先前的研究发现，SIRE位点（基质溶素IL-1响应元件）是参与抑制IL-1诱导MMP-3的抑制元件。其他人也发现这个位点是一个常见的5T/6T多态性，其中6T位点是一个更有效的抑制元件。该位点的基因型与MMP-3的组织水平以及许多疾病的易感性或严重程度有关。在心血管疾病（一种与牙周炎相关的疾病）中，高表达的5T等位基因的纯合性与心肌梗死和动脉瘤相关，而低表达的6T等位基因与动脉粥样硬化相关。因此，很明显，必须严格控制该基因的调节以维持正确的组织稳态，并且了解这些控制机制对各种病理都很重要。我们最近发现与SIRE位点结合的蛋白包括NF-kappaB p50、p65和ZBP-89。我们最近也发现，从牙周炎患者分离的人牙龈成纤维细胞中，IL-1诱导MMP-3被IL-4抑制。本申请的具体目的是：1)研究转录因子与MMP-3启动子多态位点相互作用的作用；2)确定IL-4抑制MMP-3表达的机制。在此过程中，我们希望获得有关MMP-3调控的复杂基因调控机制的信息，同时也继续为PCOM的研究环境做出贡献，并为其学生的研究，特别是分子生物学的培训做出贡献。