Extracellular Matrix in Mice Lacking Thrombospondin 2

说明(申请人提供)：凝血酶敏感蛋白2(TSP2)是一种 调节细胞功能的胞外蛋白，如黏附， 通过与生长因子相互作用的能力进行迁移和扩散， 细胞因子、蛋白水解酶和大量细胞表面受体。老鼠 LASK TSP2显示了许多看似无关的缺陷，包括异常 有结构的胶原纤维，成纤维细胞黏附减少，出血障碍， 以及以血管增多为特征的对损伤的反应。这个 这项建议的目的是了解这种不同的表型是如何导致 因为没有任何一种蛋白质。更根本的是，我们希望学到 更多关于蛋白水解酶在细胞黏附、控制血管生成中的作用 和骨生长，参与正常的血小板形成和 聚集，以及伤口愈合的过程。计划中的实验包括：1) 基质金属蛋白酶MMP2与TSP2和TSP2相互作用研究 细胞表面；2)MMP2在异物反应中的作用；3)血小板 与内皮下层的形成和相互作用；4)血管内皮细胞形成机制 TSP2抑制血管生成和骨生长，即通过凋亡而不是通过 抑制细胞增殖；5)TSP表型的评价 1/TSP2双缺失小鼠，以及每种蛋白缺失的贡献 通过局部基因治疗确定的表型。这些实验已经 开发改善伤口愈合的方法的潜力，以及 植入的生物传感器和输送装置在人体中的性能。

DESCRIPTION (provided by applicant): Thrombospondin 2 (TSP2) is an extracellular protein that modulates cell functions such as adhesion, migration, and proliferation by its ability to interact with growth factors, cytokines, proteases, and a large number of cell-surface receptors. Mice that lack TSP2 display a number of seemingly unrelated defects including abnormally structured collagen fibrils, reduced fibroblast adhesion, a bleeding disorder, and a response to injury that is characterized by increased vascularity. The purpose of this proposal is to understand how this diverse phenotype can result from the absence of a single protein. More fundamentally, we expect to learn more about the role of proteases in cell adhesion, the control of angiogenesis and bone growth, the factors involved in normal platelet formation and aggregation, and the course of wound healing. Planned experiments include: 1) studies of the interaction of a matrix metalloproteinase, MMP2, with TSP2 and the cell surface; 2) the role of MMP2 in the foreign body response; 3) platelet formation and interaction with the sub-endothelium; 4) the mechanism of inhibition of angiogenesis and bone growth by TSP2, i.e. by apoptosis versus by inhibition of cell proliferation; and 5) an evaluation of the phenotype of TSP 1 /TSP2 double-null mice, and of the contribution of the lack of each protein to the phenotype as determined by local gene therapy. These experiments have the potential to develop the means to improve wound healing, and the performance of implanted biosensors and delivery devices, in human subjects.