CRYPTIC DOMAINS OF COLLAGEN IV IN TUMOR GROWTH

描述：（申请人的描述） 这项提议的主要目的是检验一个假设， IV型胶原结构域在调节 血管生成和肿瘤生长。 这一建议是根据一系列关于 用一种新的单克隆抗体（Mab）进行的实验观察 HUIV 26）针对蛋白水解的胶原蛋白-IV。 胶原蛋白IV是一种主要的 血管内皮下基底膜的成分，因此， 内皮细胞可能通过这种富含IV型胶原的屏障侵入 有助于新血管形成。 重要的是， 生化调控信息隐藏在三维空间中 尚未详细研究特定ECM分子的结构。 事实上， 很少有直接证据表明，ECM 重塑有助于血管生成。 为此，我们的初步调查结果 提示MAb HUIV 26特异性识别胶原蛋白中的隐蔽结构域， IV，其在成熟的天然胶原-IV中不可接近，但暴露于 蛋白水解后。 此外，我们的发现表明，这种HUIV 26神秘的 结构域特异性地暴露在血管内皮下基底膜内， 体内肿瘤相关血管。 此外，初步结果 提示Mab HUIV 26全身给药抑制血管生成， 肿瘤生长 根据这些初步调查结果， IV型胶原的蛋白水解可能代表了一种独特的机制， 生物化学信息被传递到内皮细胞， 调节血管生成和肿瘤生长。 因此，识别和 这个隐蔽结构域的功能特征，可能导致 发展新的治疗方法治疗病理性 新血管形成和恶性肿瘤生长。

DESCRIPTION: (Applicant's Description) The major objective of this proposal is to test the hypothesis that a cryptic domain of collagen-IV plays a fundamental role in the regulation of angiogenesis and tumor growth. This proposal is based on a series on observations from experiments performed with a novel monoclonal antibody (Mab HUIV 26) directed to proteolyzed collagen-IV. Collagen-IV is a major component of the subendothelial basement membrane of blood vessels, and thus, endothelial cell invasion through this collagen-IV rich barrier likely contributes to neovascularization. Importantly, the possibility that biochemical regulatory information is hidden within the three dimensional structure of specific ECM molecules has not been explored in detail. In fact, little direct evidence is available concerning the mechanism by which ECM remodeling contributes to angiogenesis. To this end, our preliminary findings suggest that Mab HUIV26 specifically recognizes a cryptic domain in collagen- IV which is inaccessible within mature native collagen-IV but is exposed following proteolysis. Moreover, our finding suggest that this HUIV26 cryptic domain is specifically exposed within the subendothelial basement membrane of tumor associated blood vessel in vivo. Furthermore, preliminary results suggest that systemic administration of Mab HUIV26 inhibits angiogenesis and tumor growth. Based on these preliminary findings, it is possible that proteolysis of collagen-IV may represent a unique mechanism by which cryptic biochemical information is transferred to endothelial cells, thereby regulating angiogenesis and tumor growth. Thus, the identification and functional characterization of this cryptic domain, may lead to the development of novel therapeutic approaches for the treatment of pathological neovascularization and malignant tumor growth.