ROLE OF METALLO-PROTEINASES IN MAMMARY GLAND REMODELING

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 基质金属蛋白酶（MMP）基因家族的细胞外基质（ECM）降解蛋白酶与乳腺肿瘤进展的发病机制有关，但也在正常组织重塑中发挥作用。该项目测试的假设，MMPs是乳腺上皮细胞，脂肪形成基质和细胞外基质之间的相互作用的重要贡献者。我们在转基因小鼠和乳腺培养物中进行了遗传分析，结果表明基质细胞和乳腺上皮细胞表达的MMP改变了发育过程中乳腺的细胞微环境，并导致肿瘤进展。我们希望解决的分子机制，这些基质金属蛋白酶编排之间的间充质和上皮车厢的串扰。现在很清楚，改变MMP水平和活性会影响乳腺上皮祖细胞、导管细胞和基质细胞的表型和行为。我们建议研究这些改变的结构基础的形态发生，分化，迁移和侵入行为中分离和相互作用的细胞群体中的各种微环境配置的培养模型，并在体内分支形态发生使用野生型和MMP突变小鼠的细胞。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Extracellular matrix (ECM)-degrading proteinases of the matrix metalloproteinase (MMP) gene family have been implicated in the pathogenesis of breast neoplastic progression, yet also play a role in normal tissue remodeling. This project tests the hypothesis that MMPs are essential contributors to the interaction between mammary epithelial cells, the adipogenic stroma and the extracellular matdx. We have used genetic analysis in transgenic mice and mammary cultures, to show that MMPs expressed by stromal cells and mammary epithelial cells alter the cellular microenvironment in the mammary gland during development and lead to neoplastic progression. We wish to address the molecular mechanisms by which these MMPs orchestrate the cross-talk between the mesenchymal and epithelial compartments. It is now clear that altering MMP levels and activity affects the phenotype and behavior of mammary epithelial progenitor and ductal cells and stromal cells. We propose to study the structural basis of these alterations in morphogenesis, differentiation, and migratory and invasive behavior in separated and interacting populations of cells in various microenvironmental configurations in culture model and during in vivo branching morphogenesis using cells from wild type and MMP mutant mice.