Site Specific Interactions and Collagen Self Assembly

描述（由申请人提供）：这项竞争性更新的总体目标是研究抑制胶原原纤维形成的新方法，以减少病理性纤维化沉积物的积累。目前提出的项目是从美国国立卫生研究院支持的研究中发展而来的，这些研究表明，胶原原纤维（纤维化组织的主要成分）的形成可以被抑制剂抑制，这种抑制剂阻断了驱动胶原蛋白自组装的位点特异性胶原/胶原相互作用。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，有可能减少纤维化组织的形成。为了验证这一假设，我们提出了三个具体目标：(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)在体外稳定和测试所选抑制剂抑制胶原原纤维形成的潜力。(3)在瘢痕疙瘩样模型中确定局部纤维化抑制剂的有效性。我们将采用实验模型来验证我们的假设，包括单克隆抗体和合成肽，它们特异性地结合到参与胶原/胶原相互作用的位点上。我们计划通过体外和体内分析来确定所提出的抑制剂的临床效用。虽然我们的研究将探讨所提出的方法对抑制皮肤局部纤维化的有用性，但我们希望我们的研究结果将对限制其他组织中纤维化沉积物的形成产生广泛的积极影响。这个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原纤维的过度积累。因此，我们提出的研究在预防纤维化破坏性影响方面的预期广泛影响是很高的。

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.