Transcriptional Regulation of Matrix Metalloproteinase-3

产品说明：在牙周炎中，炎性细胞因子IL-1的水平高并且与疾病的严重程度相关，而抗炎性IL-4的水平低或不可检测，并且IL-4水平的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丧失和牙槽骨破坏。MMP-3具有广泛的底物特异性，并可激活其他MMP前体。它在患病部位的水平增加，并且水平与严重程度和进展相关。先前的研究鉴定了SIRE位点（基质溶解素IL-1反应元件）作为参与抑制MMP-3的IL-1诱导的阻遏元件。其他人也将该位点确定为常见的5 T/6 T多态性，其中6 T位点是更有效的阻遏元件。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性有关。在心血管疾病（与牙周炎相关的疾病）中，高表达的5 T等位基因的纯合性与心肌梗死和动脉瘤相关，而低表达的6 T等位基因与动脉粥样硬化相关。因此，很明显，该基因的调控必须严格控制，以保持正确的组织稳态，了解这些控制机制是重要的各种病理。我们最近发现与SIRE位点结合的蛋白质包括NF-κ B p50和p65以及ZBP-89。我们最近还发现，IL-1诱导MMP-3的抑制IL-4在人牙龈成纤维细胞从牙周炎患者分离。本申请的具体目的是：1）研究与MMP-3启动子中的多态性SIRE位点相互作用的转录因子的作用，和2）确定IL-4抑制MMP-3表达的机制。通过这样做，我们希望获得有关MMP-3调控中涉及的复杂基因调控机制的信息，但也继续为PCOM的研究环境和学生在一般研究中的培训做出贡献，特别是分子生物学。

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.