Regulatory mechanisms of collagen XII in establishing Achilles tendon hierarchical structure and function in postnatal development and in mechanotransduction
Formation of tendon during tendon development and healing is reliant on coordination of multiscale regulatory governing processes such as formation of fibrils from collagen molecules, assembly of fibril bundles to form fibers, and recruitment of fibers to form fascicles. Collagen XII is a Fibril-Associated Collagen with Interrupted Triple Helices (FACIT) and is primarily expressed during tendon growth and development and following injury. Collagen XII interacts with collagen I fibrils and cell surfaces and its localization to form flexible bridges between collagen fibrils implicates its role in regulating collagen I fibrillogenesis, fibril organization, and interactions with other extracellular matrix constituents. However, the mechanisms by which collagen XII deficiency disrupts formation of tendon hierarchical structure during postnatal development remain unknown. Therefore, the objective of this proposal is to establish the mechanisms involving collagen XII regulation of tendon hierarchical structure, mechanical function and composition throughout postnatal development and how collagen XII impacts mechanotransduction. We will use our novel tendon-targeted Col12a1 knockout and inducible Col12a1 knockdown mouse models for investigation of the regulatory roles of collagen XII throughout Achilles tendon development and after sciatic nerve resection to unload the tendon. We will perform comprehensive multiscale structural, functional, and compositional assays using our innovative mouse models in the following to elucidate the mechanistic roles of collagen XII in regulating hierarchical assembly of tendon required for function during postnatal development and to define the regulatory mechanisms involving collagen XII in mechanotransduction. Understanding these targeted role of collagen XII will advance understanding of its contributions to tendon matrix and cell regulation which will be valuable for efforts to leverage mechanisms of development to improve tendon healing and mimic tendon structure with tissue engineering