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.
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.
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