PROTEOLYZED COLLAGEN IN ANGIOGENESIS AND APOPTOSIS

描述：(改编自调查人员的摘要)主要目标 这项建议的目的是定义胶原蛋白降解的具体作用 血管生成过程中的组织重塑。调查员提议检查 间质蛋白水解性修饰的功能意义 I型胶原，是血管细胞外基质的主要成分， 历来被认为是调节组织的结构成分 形态发生和稳定性。血管生成被认为依赖于 细胞黏附和蛋白分解两种机制。然而，到目前为止，几乎没有 关于细胞黏附受体和蛋白质降解的已知 细胞外基质(ECM)成分在血管内皮细胞 体内血管生成的调控。潜在的细胞和生化 蛋白水解性降解胶原蛋白的机制及其结果 片段可以作为血管整合素α和β3的配基， 促进内皮细胞存活和血管生成将被研究。 假设基质金属蛋白酶(MMPs)是主要的一类 能够特异性降解间质胶原的酶的数量正在上升 在体内调节和选择性地与血管新生血管相关。 将确定升高的MMPs水平是否表达在 一种蛋白水解性活性形式，可启动蛋白水解物的形成 血管生成血液即刻微环境中的间质胶原 船只。胶原蛋白降解的能力可以揭示 神秘的粘连序列，提供了一种生理上重要的配体 对于结扎所需的血管整合素α-β3介导的事件 将测试内皮细胞存活和血管生成的情况。自.以来 血管生成在多种正常和病理性血管病变中起着关键作用。 过程，理解调节这个过程的分子事件是 最重要的是，不仅对我们对 血管生成，也有助于设计新的治疗策略 以新生血管为特征的疾病。因此，这项研究 应该提供新的信息来弥合我们对 体内调节新血管形成的复杂机制和 为蛋白水解胶原蛋白的特定作用提供了第一个证据 内皮细胞存活和血管生成的调控。

DESCRIPTION: (adapted from the investigator's abstract) The major objective of this proposal is to define a specific role for collagen degradation and tissue remodeling during angiogenesis. The investigator proposes to examine the functional significance of proteolytic modification of interstitial collagen type-I, a major component of the vascular extracellular matrix that has historically been considered as a structural component regulating tissue morphogenesis and stability. Angiogenesis has been suggested to depend on both cell adhesion and proteolytic mechanisms. However, to date, little is known concerning how cell adhesion receptors and proteolytically degraded extracellular matrix (ECM) components function cooperatively in the regulation of angiogenesis in vivo. The potential cellular and biochemical mechanisms by which proteolytically degraded collagen and resulting fragments can function as a ligand for vascular integrin alphav beta3, potentiating endothelial cell survival and angiogenesis will be examined. The hypothesis is that matrix metalloproteinases (MMPs), the primary class of enzymes capable of specifically degrading interstitial collagen, are up regulated and selectively associated with angiogenic blood vessels in vivo. It will be determined whether the elevated levels of MMPs are expressed in a proteolytically active form that could initiate the formation of proteolyzed interstitial collagen in the immediate microenvironment of angiogenic blood vessels. The ability of proteolytic degradation of collagen to reveal cryptic adhesive sequences that provide a physiologically important ligand for vascular integrin alphav beta3-mediated event necessary for the ligation of endothelial cell survival and angiogenesis will be tested. Since angio-genesis plays a critical role in a variety of normal and pathological processes, understanding the molecular events that regulate this process is of paramount importance, not only to our basic understanding of angiogenesis, but also to the design of novel strategies for the treatment of diseases characterized by neovascularization. Therefore, this study should provide new information to bridge the gap in our understanding of the complex mechanisms that regulate new blood vessels formation in vivo and provide the first evidence for a specific role for proteolyzed collagen in the regulation of endothelial cell survival and angiogenesis.