Intervertebral disc (IVD) degeneration is a debilitating disorder implicated in the pathogenesis of low back pain with associated medical costs that can exceed $100 billion annually. The overall goal of the proposed research is to introduce 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. Current therapies fail to integrate both structural repair and analgesia. Further, several analgesics are cytotoxic so that developing new therapeutic agents and strategies are a major research priority. The large vacuolated notochordal cells (NCs) in developing animals orchestrate patterning of the IVDs, vertebrae and surrounding spinal structures. Humans and other species that do not retain NCs into adulthood exhibit age related IVD degeneration and researchers have long sought to answer why NCs are lost in humans at young ages. The literature now indicates NCs are progenitor cells and suggests their early disappearance in humans is associated with their differentiation to small chondrocytic nucleus pulposus cells (SNPCs). For the first time, we have a bioreactor and culture methods capable of differentiating NCs into SNPCs so that we can derive therapies from NCs and explore mechanisms for their differentiation. The proposed studies provide a new paradigm for designing an integrated therapeutic intervention derived from trophic agents secreted by NCs to create structure and symptom modifying therapies capable of restoring IVD function and preventing discogenic pain by inhibition of neurovascular growth into the IVD.
Aim 1 will determine microenvironment conditions capable of retaining NC phenotype, characterize the phenotypic stability of important genes and proteins of bioactive molecules produced by NCs, and isolate pathways involved in NC differentiation.
Aim 2 is a series of descriptive and mechanistic studies that assess therapeutic potential of proteins secreted by NCs with dependent variables that focus on pain inhibition by limiting neurovascular invasion and promoting structural restoration.
Aim 3 evaluates designed 'cocktail'treatments for their effects promoting anabolism and inhibiting discogenic pain or predictors of pain in human ex vivo organ culture models and rat in vivo discogenic pain models. This project is significant because of the translational potential to the highly clinically significant problem of discogenic back pain. The approach is innovative because it investigates factors important in developmental biology and introduces them for therapeutic effect using descriptive and mechanistic studies. We focus on therapeutic potential with mechanistic testing and screening studies using novel human organ culture and rat discogenic pain models. Innovation and significance are also high because determining optimal microenvironmental culturing conditions of NCs will help accelerate the growing body of research on these underexplored cells.
Painful intervertebral disc degeneration has a tremendously large clinical and economic impact, and these investigations follow a rational approach to develop new treatments derived from notochordal cells, which are underexplored cells essential in disc development. The proposed studies isolate microenvironmental factors responsible for differentiating notochordal cells into small chondrocytic nucleus pulposus cells and identify trophic factors secreted by notochordal cells that can be used therapeutically to enhance structural repair and reduce painful symptoms by inhibiting neurovascular ingrowth. 'Cocktail'treatments are designed using these bioactive proteins and their therapeutic potential is screened using human organ culture and in vivo discogenic pain models. This project is targeted towards determining early and minimally invasive treatments for painful disc disease, and has high significance and innovation in the identification of novel therapeutic agents, the combined ex vivo and in vivo screening strategy that maximizes human relevance and minimizes animal usage, and in the exploration of notochordal cell differentiation.
|Likhitpanichkul, Morakot; Torre, Olivia M; Gruen, Jadry et al. (2016) Do mechanical strain and TNF-Î± interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells? J Biomech 49:1214-20|
|Walter, B A; Purmessur, D; Moon, A et al. (2016) Reduced tissue osmolarity increases TRPV4 expression and pro-inflammatory cytokines in intervertebral disc cells. Eur Cell Mater 32:123-36|
|Iatridis, James C; Kang, James; Kandel, Rita et al. (2016) New Horizons in Spine Research: Disc biology, spine biomechanics and pathomechanisms of back pain. J Orthop Res 34:1287-8|
|Vo, Nam V; Hartman, Robert A; Patil, Prashanti R et al. (2016) Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res 34:1289-306|
|Lai, Alon; Moon, Andrew; Purmessur, Devina et al. (2016) Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo. Spine J 16:420-31|
|Illien-JÃ¼nger, Svenja; Lu, Young; Qureshi, Sheeraz A et al. (2015) Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice. PLoS One 10:e0116625|
|Gantenbein, Benjamin; Illien-JÃ¼nger, Svenja; Chan, Samantha C W et al. (2015) Organ culture bioreactors--platforms to study human intervertebral disc degeneration and regenerative therapy. Curr Stem Cell Res Ther 10:339-52|
|Walter, Benjamin A; Likhitpanichkul, Morakot; Illien-Junger, Svenja et al. (2015) TNFÎ± transport induced by dynamic loading alters biomechanics of intact intervertebral discs. PLoS One 10:e0118358|
|Lai, Alon; Moon, Andrew; Purmessur, Devina et al. (2015) Assessment of functional and behavioral changes sensitive to painful disc degeneration. J Orthop Res 33:755-64|
|Risbud, Makarand V; Schoepflin, Zachary R; Mwale, Fackson et al. (2015) Defining the phenotype of young healthy nucleus pulposus cells: recommendations of the Spine Research Interest Group at the 2014 annual ORS meeting. J Orthop Res 33:283-93|
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