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

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

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 res...

## Key facts

- **NIH application ID:** 10910875
- **Project number:** 5F31AR083255-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Steven DiStefano
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910875

## Citation

> US National Institutes of Health, RePORTER application 10910875, Regulatory Mechanisms of Collagen XII in Establishing Achilles Tendon Hierarchical Structure and Function in Postnatal Development and Healing (5F31AR083255-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10910875. Licensed CC0.

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