Intervertebral disc (IVD) degeneration is a debilitating disorder implicated in the pathogenesis of low back pain with associated costs that can exceed $100 billion annually. The overall goal of the parent award is to develop novel therapeutic agents and strategies for use in a minimally invasive manner to limit degeneration, restore IVD structure, and reduce painful conditions of degenerative disc disease. Our year 1 preliminary data of the parent grant highlight the crucially important role of proteoglycan structure and sulfation pattern in cues to inhibit neurovascular invasion into the IVD. As important as proteoglycans are in the IVD matrix, there has not been a major advance in the characterization of glycosaminoglycan (GAG) structure and sulfation patterns in many years. This BIRT introduces new technologies to the IVD research field that allow characterization of proteoglycans, beyond GAG content measurements, to include features that play important bioactive roles. This BIRT proposal develops a new collaboration between Dr. James Iatridis at Mount Sinai and Dr. Robert Linhardt at Rensselaer Polytechnic Institute. We combine expertise in IVD research with a proteoglycan expert in order to develop and apply novel techniques for the characterization and isolation of GAGs in the IVD. We believe that IVD and cartilage research is slowed by the characterization of proteoglycans by their glycosaminoglycan (GAG) content alone. The structure or sulfation patterns of proteoglycans are responsible for many important bioactive roles including neurovascular growth.
Aim 1 is to characterize the GAG profile of human IVDs with growth, aging and disease across IVD regions using human autopsy samples and surgical samples from painful IVDs during discectomy surgery.
Aim 2 is to characterize the effects of different GAG structures (CS4, CS6, KS& DS) that are isolated from human IVDs on neurovascular growth using cell culture models. This project is significant because the GAG structure and sulfation patterns are underexplored in cartilaginous tissues and these concepts are highly relevant to the problem of discogenic back pain. The approach is innovative because it includes advanced glycomics measurements. Dissemination milestones involve teaching these novel technologies to graduate students at both RPI and Mount Sinai and also introducing these techniques and new science to IVD researchers at an international research meeting.
Painful intervertebral disc degeneration has a tremendously large clinical and economic impact. Proteoglycans are among the most abundant and important matrix proteins in the intervertebral disc, and while their content has been well-studied there is little information on proteoglycan structure and sulfation patterns which has been largely overlooked and has important bioactive roles. The proposed BIRT studies form a new collaboration that brings advanced assays for the isolation and characterization of proteoglycans to intervertebral disc research. We will characterize proteoglycan profiles of intervertebral discs across species, with aging and in painful conditions and identify important proteoglycan structures responsible for neurovascular invasion and repulsion. Dissemination milestones will help inform the broader research community of these techniques and findings.
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