CRYPTIC DOMAINS OF COLLAGEN IV IN TUMOR GROWTH

描述：(申请人描述) 这一提议的主要目标是检验一种神秘的 IV型胶原蛋白的结构域在细胞免疫调节中起重要作用 血管生成与肿瘤生长。这项建议是基于一系列 用一种新型单抗(Mab)进行实验观察 HUIV 26)针对蛋白水解胶原-IV。IV型胶原是一种主要的 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型胶原的屏障侵袭 有助于新生血管的形成。重要的是，有可能 生化调控信息隐藏在三维空间中 具体的ECM分子的结构还没有详细探讨。事实上, 关于ECM的机制，几乎没有直接的证据 重塑有助于血管生成。为此，我们的初步调查结果 提示单抗HUIV26特异性识别胶原蛋白中的一个隐蔽结构域- IV在成熟的天然胶原蛋白-IV中不能获得，但暴露在 在蛋白质分解之后。此外，我们的发现表明，这种HUIV26隐秘 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 提示全身应用单抗HUIV26可抑制血管生成和 肿瘤生长。根据这些初步调查结果，有可能 IV型胶原的蛋白分解可能代表了一种独特的机制，通过这种机制 生化信息被传递到内皮细胞，从而 调节血管生成和肿瘤生长。因此，身份识别和 对这个神秘区域的功能表征，可能会导致 病理性疾病治疗新方法的发展 新生血管与恶性肿瘤生长。

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.