MMP9 Modulation of Uterine Contraction and Birth Timing

项目摘要 基质金属蛋白酶2和金属蛋白酶9（MMP 2/9）已被证明在一个细胞周期中发挥积极作用。 各种细胞反应，包括子宫收缩的调节。潜在的分子 驱动这些效应的机制目前尚不清楚。本提案的总体目标是了解 MMP 9促进子宫收缩的机制，并确定是否特异性抑制MMP 9 促进子宫静止。中心假设是MMP 9升高到早产儿中的水平， 患者的子宫收缩足以增加人子宫组织的收缩反应并促使早产。 该提议将确定纯化的MMP 9是否促进子宫收缩，以及MMP 9的特异性抑制是否促进子宫收缩。 促进足月和早产人子宫组织的子宫静止。将进行实验， 确定MMP 9抑制是否可以在早产动物模型中延迟分娩。最后，该提案将 确定MMP 9抑制是否通过减少细胞内钙瞬变促进子宫静止， 应用蛋白质组学技术鉴定MMP 9作用的新机制。这些数据预计将在 重要的是，因为它们将为未来的实验提供基础，以确定MMP 9或 相关通路抑制剂可以作为药物靶点，促进子宫静止， 早产人数。

PROJECT SUMMARY Matrix Metalloproteinases 2 and Metalloproteinase 9 (MMP2/9) have been shown to play active roles in a variety of cellular responses, including the regulation of uterine contraction. The underlying molecular mechanisms driving these effects are currently unknown. The overall objective of this proposal is to understand the mechanisms by which MMP9 promotes uterine contraction and to determine if specific inhibition of MMP9 promotes uterine quiescence. The central hypothesis is that elevation of MMP9 to levels seen in preterm patients is sufficient to increase the contractile response in human uterine tissue and drive preterm parturition. This proposal will determine if purified MMP9 promotes uterine contraction and if specific inhibition of MMP9 promotes uterine quiescence in term and preterm human uterine tissue. Experiments will be performed to determine if MMP9 inhibition can delay parturition in preterm animal models. Finally, this proposal will determine if MMP9 inhibition promotes uterine quiescence by decreasing intracellular calcium transients and apply proteomic technologies to identify novel mechanisms of MMP9 action. These data are expected to be significant because these they will provide the foundation for future experiments to determine if MMP9 or related pathway inhibitors can serve as druggable targets to promote uterine quiescence and reduce the number preterm births.