Site Specific Interactions and Collagen Self Assembly

描述（由申请方提供）：该竞争性更新的总体目的是研究抑制胶原纤维形成作为减少病理性纤维化沉积物积累的新方法。目前提出的项目是从我们的NIH支持的研究发展而来的，该研究表明，胶原纤维（纤维化组织的主要成分）的形成可以被抑制剂抑制，该抑制剂阻断了驱动胶原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，可以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的目标：（1）选择具有特异性亲和力的抑制剂，用于结合控制胶原I自组装的位点。(2)在体外稳定并测试所选抑制剂抑制胶原原纤维形成的潜力。(3)确定瘢痕疙瘩样模型中局部纤维化抑制剂的有效性。我们将采用的实验模型来测试我们的假设将包括单克隆抗体和合成肽，这些抗体和合成肽特异性地结合到参与胶原/胶原相互作用的位点。我们计划通过采用体外和体内分析来确定所提出的抑制剂的临床效用。虽然我们的研究将调查所提出的方法抑制皮肤局部纤维化的有用性，但我们预计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。这一概念是基于这样的事实，即无论病因如何，纤维化过程总是包括胶原纤维的过度积累。因此，我们提出的研究对预防纤维化的破坏性影响的预期广泛影响很高。 公共卫生相关性：纤维化是一种严重的医学问题，影响所有富含胶原蛋白的结缔组织。由于纤维化的标志之一是过度积累的胶原纤维，拟议的研究的目的是开发新的方法来限制纤维化，通过抑制细胞外过程的胶原纤维组装。由于我们的研究结果将为纤维化引起的病理变化的新治疗方法奠定基础，因此我们提出的研究对公共卫生的相关性很高。

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. PUBLIC HEALTH RELEVANCE: Fibrosis is a serious medical problem that affects all collagen-rich connective tissues. Because one of the hallmarks of fibrosis is excessive accumulation of collagen fibrils, the objective of the proposed study is to develop novel approaches to limit fibrosis by inhibiting the extracellular process of collagen fibril assembly. Since results of our study will establish the basis for new treatments of pathological changes caused by fibrosis, the relevance of our proposed research for public health is high.