Transcriptional Regulation of Matrix Metalloproteinase-3

基质金属蛋白酶 3 的转录调控

• 批准号: 6848196
• 负责人: RUTH C BORGHAEI
• 金额: $ 21.83万
• 依托单位: PHILADELPHIA COLLEGE OF OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6848196
• 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，炎症性细胞因子IL-1水平较高，与疾病的严重程度相关，而抗炎IL-4的水平低或不可检测，并且IL-4水平降低与严重程度的增加相关。 IL-1通过增加基质金属蛋白酶的表达而导致附着和肺泡骨破坏的丧失。 MMP-3具有广泛的底物特异性，可以激活其他Pro-MMP。在患病部位的水平增加中，水平与严重程度和进展相关。先前的研究将父亲位点（Stromelysin IL-1响应元件）确定为抑制MMP-3诱导IL-1诱导的阻遏物元件。其他人也将该站点确定为常见的5T/6T多态性，而6T站点是更有效的阻遏物元素。该部位的基因型与MMP-3的组织水平以及多种疾病的敏感性或严重程度有关。在心血管疾病（与牙周炎相关的疾病）中，较高表达的5T等位基因的纯合性与心肌梗死和动脉瘤有关，而低表达的6T等位基因与动脉粥样硬化有关。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于多种病理学很重要。我们最近发现，与父亲部位结合的蛋白质包括NF-kappab P50和P65和ZBP-89。我们最近还表明，从牙周炎患者中分离出的人牙龈成纤维细胞中，IL-1诱导MMP-3的IL-1抑制。该应用的具体目的是：1）研究MMP-3启动子中与多态性父亲位点相互作用的转录因子的作用，以及2）确定IL-4通过IL-4的抑制MMP-3表达的机理。在此过程中，我们希望获得有关MMP-3调节涉及的复杂基因调节机制的信息，但也继续为PCOM的研究环境以及对整个研究的学生培训，尤其是分子生物学的培训。