Site Specific Interactions and Collagen Self Assembly

描述(由申请人提供)：本次竞争性更新的总体目标是研究抑制胶原纤维形成作为减少病理性纤维沉积堆积的新方法。目前提出的项目是从我们由NIH支持的研究演变而来的，这些研究表明，胶原纤维的形成可以被抑制，这种抑制物可以阻止特定部位的胶原/胶原相互作用，从而驱动胶原的自组装。因此，这里提出的主要假设是，通过干扰胶原纤维形成的细胞外过程的初始步骤，有可能减少纤维组织的形成。为了验证这一假设，我们提出了三个具体的目标：(1)选择具有特定亲和力的抑制剂来结合控制I型胶原自组装的位点。(2)体外稳定和检测所选抑制剂对胶原纤维形成的抑制作用。(3)在瘢痕疙瘩模型中确定局部纤维化抑制剂的有效性。我们将用来验证我们的假设的实验模型将包括单抗和合成肽，它们专门结合到参与胶原蛋白/胶原蛋白相互作用的部位。我们计划通过体外和体内分析来确定所建议的抑制剂的临床效用。虽然我们的研究将调查拟议的方法在抑制皮肤局部纤维化方面的有效性，但我们预计我们的研究结果将对限制其他组织中纤维沉积的形成产生广泛的积极影响。这一概念是基于这样一个事实，即无论病因如何，纤维化过程总是包括胶原纤维的过度堆积。因此，我们提议的研究对预防纤维化的破坏性影响的预期广泛影响很高。

DESCRIPTION (provided by applicant): The overall aim of this competing renewal is to study the inhibition of the formation of collagen fibrils as the novel approach to reduce accumulation of pathological fibrotic deposits. The currently proposed project has evolved from our NIH-supported studies, which demonstrated that the formation of collagen fibrils, a main component of fibrotic tissues, can be suppressed by inhibitors that block site-specific collagen/collagen interactions that drive collagen self-assembly. Thus, the main hypothesis presented here is that by interfering with the initial steps of the extracellular process of collagen fibril formation, it is possible to reduce the formation of fibrotic tissue. To test this hypothesis, we propose three Specific Aims: (1) to select inhibitors with specific affinities for binding the sites that control collagen I self- assembly. (2) To stabilize and test the selected inhibitors in vitro for their potential to inhibit collagen fibril formation. (3) To determine the effectiveness of inhibitors of localized fibrosis in a keloid-like model. The experimental model we will employ to test our hypothesis will include monoclonal antibodies and synthetic peptides that specifically bind to the sites that participate in the collagen/collagen interaction. We plan to determine the clinical utility of the proposed inhibitors by employing in vitro and in vivo analyses. Although our study will investigate the usefulness of the proposed method to inhibit localized fibrosis in skin, we expect that the results of our study will have a broad positive impact on limiting the formation of fibrotic deposits in other tissues. This notion is based on the fact that, irrespective of etiology, the fibrotic process always includes excessive accumulation of collagen fibrils. Thus, the expected broad impact of our proposed study on preventing devastating effects of fibrosis is high.