# Collagen Proteostasis in Health and Disease > **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $680,325 ## Abstract Collagen is the most abundant protein in animals, constituting up to one-third of total protein in humans. As the major proteinaceous component of tissues ranging from bone and skin to cartilage and basement mem- branes, it constitutes the molecular scaffold for animal life. This ubiquitous protein is uniquely challenging for cells to produce, requiring highly coordinated intracellular processes of synthesis, folding, assembly, and qual- ity control. Owing to the hierarchical nature of collagenous extracellular matrices, the physical and biochemical properties of such tissues are fundamentally defined by these upstream, intracellular processes. Defects, whether genetic or otherwise, that are detrimental to any aspect of collagen proteostasis can impact the health or function of collagen-producing cells and also propagate to extracellular matrices, leading to diseases known as the collagenopathies. Unfortunately, these diseases almost universally lack effective, disease-modifying therapies. Current therapeutic approaches to the collagenopathies focus on regenerative interventions, efforts to strengthen the extracellular matrix itself, or palliative care. None of these strategies aims to address the up- stream issue leading to disease: a failure to properly fold and quality control collagen molecules themselves. If the breakdown of collagen proteostasis could be effectively addressed, the downstream symptoms targeted by current clinical strategies would be alleviated. Indeed, proteostasis enhancement has proven remarkably effi- cacious in many other genetic disorders, including cystic fibrosis, but it has yet to make serious inroads in the collagenopathies. One obstacle is inadequate understanding of the critical decision points in the collagen pro- teostasis network. Another issue is the challenge of pre-clinical testing of proteostasis-targeted interventions in a disease that requires robust, yet biochemically amenable, tissue model systems for discovery efforts. This R01 proposal seeks to address these knowledge gaps, both identifying and elucidating key mech- anisms of intracellular folding and quality control, and assessing the therapeutic potential of proteostasis net- work-targeted interventions in the collagenopathies. In Aim 1, functions of the highly conserved procollagen N- glycan in promoting folding, enabling quality control, and identifying when folded procollagens are ready for secretion will be elucidated, via comprehensive work both in cells and in vivo that will reveal the molecular mechanisms of collagen glycoproteostasis. The expectation is to demonstrate that the long-ignored procolla- gen N-glycan is actually the critical fulcrum of collagen proteostasis. In Aim 2, a state-of-the-art, 3D cartilage- in-a-dish model system is deployed to enable robust testing of proteostasis network-targeted therapies for the collagenopathies. Combined with mechanistic studies to elucidate the biochemistry of dysregulated collagen proteostasis... ## Key facts - **NIH application ID:** 10981586 - **Project number:** 1R01AR082995-01A1 - **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY - **Principal Investigator:** Matthew Donald Shoulders - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $680,325 - **Award type:** 1 - **Project period:** 2024-09-04 → 2029-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10981586 ## Citation > US National Institutes of Health, RePORTER application 10981586, Collagen Proteostasis in Health and Disease (1R01AR082995-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10981586. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*