Project Summary/Abstract Chronic low back pain (cLBP) is a leading cause of disability globally and is thought to relate to intervertebral disc degeneration in some patients. The cartilage endplate (CEP) plays a key role in disc health by influencing nutrient transport between the avascular disc and the vertebral capillaries. By its influence on disc nutrient supply, the CEP may also influence the efficacy of cell-based biologic therapies designed to regenerate the disc, as these therapies increase intradiscal nutrient demands. The premise of this proposal is that non-invasive assessment of CEP composition could provide insight into disc degeneration etiology and guide patient selection for cell-based biologic therapies, in turn helping to address the global health burden associated with cLBP. A novel imaging biomarker of CEP composition—the mean CEP T2* relaxation time measured using ultra- short echo time (UTE) MRI—has recently been shown to correlate with aspects of CEP composition influencing nutrient transport to the disc and the extent of disc degeneration in patients with cLBP. This non-invasive biomarker has major implications for elucidating the role of the CEP in disc degeneration/regeneration. However, the MR signal generated by the CEP depends on its in situ orientation relative in the MRI bore. Differences in T2* caused by orientation during imaging could exceed those associated with biochemical or microstructural deterioration, thus confounding accurate analysis. Without understanding the effects of orientation on CEP T2* values, researchers—and eventually clinicians—cannot accurately assess CEP composition in patients. The studies proposed here address these limitations and facilitate the development and clinical translation of MRI-based biomarkers of CEP composition independent of inter- and intra-individual anatomic variations in CEP orientation. Aim 1a will image cadaveric motion segments with UTE MRI at varying angles to develop a calibration curve for adjusting CEP T2* values based on in situ orientation. Aim 1b will test the clinical utility of this calibration curve in clinical cohorts of patients with cLBP and asymptomatic controls imaged with UTE MRI. Aim 2 will quantify the contributions of CEP microstructure and biochemical composition to inter- and intra-CEP variations in CEP T2* values, enhancing mechanistic understanding of the factors influencing CEP T2* and thus the diagnostic interpretation of UTE-based CEP biomarkers. The proposed training plan involves developing expertise in advanced techniques in MRI, biochemical and microstructural characterization of musculoskeletal tissues, mathematical and statistical modeling, and concepts in clinical medicine with a focus on cLBP. The fellowship is supported by two sponsors—Dr. Aaron Fields (primary sponsor, Department of Orthopaedic Surgery) and Dr. Roland Krug (co-sponsor, Department of Radiology)—who have deep domain expertise in the proposed research areas. The wo...