Regulatory Mechanisms of Collagen XII in Establishing Achilles Tendon Hierarchical Structure and Function in Postnatal Development and Healing

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Project Abstract Tendon hierarchical structure dictates its ability to effectively transmit loads from muscle to bone. 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. Further, collagen XII has critical roles in the injury and regenerative responses. For instance, collagen XII co-localization with collagen I and other matrix components is present during tissue regeneration, suggesting a role in tissue cohesion. Recent data showed that collagen XII deficiency disrupts tendon structural and functional properties in mice and human disease, suggesting that collagen XII regulation is critical in tendon development and healing. However, the mechanisms by which collagen XII deficiency disrupts formation of tendon hierarchical structure during postnatal development, and recapitulation of this hierarchical structure after injury, 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 healing. We hypothesize that collagen XII-mediated mechanisms are required for establishing tendon structure and function and that these regulatory mechanisms are recapitulated after injury. To test this, 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 healing. We will perform comprehensive multiscale structural, functional, and compositional assays using our innovative mouse models in the following: Aim 1: Elucidate the mechanistic roles of collagen XII in regulating hierarchical assembly of tendon required for function during postnatal development. Aim 2: Define the regulatory mechanisms involving collagen XII during healing. Utilizing our innovative mouse models, we will define tendon-specific regulatory mechanisms involving collagen XII to provide a fundamental understanding of the acquisition of tendon structure and function and its re-establishment during healing. Comprehensive, and rigorous assessments of tendon multiscale structure, function, and composition will define the role of collagen XII throughout the progressive stages of postnatal development and the post-injury healing response. Activities described by this proposal provide a strong foundation for scientific inquiry, preparing me to make valuable contributions as an independent investigator.