Date of Award
8-19-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Chronic low back pain (LBP) affects more than 80% of Americans and causes significant disability and staggering public health costs. Despite this astonishing prevalence, there are currently no disease modifying therapies. Intervertebral disc (IVD) degeneration accounts for a considerable proportion of LBP, but the precise mechanisms driving the painful pathoanatomy are not understood. The degenerating IVD exhibits a complex array of inflammatory and physiologic changes, and many are associated with the presentation of LBP. For example, the presence of nerves and blood vessels in degenerate IVDs have been identified in patients and animals presenting with LBP symptoms. However, no studies to date have been successful in defining causative observations between intradiscal nerves and vessels and pain behavior. Degenerating IVDs express a milieu of chemokines, matrix catabolic/anabolic enzymes, and growth factors. Of these, Vascular Growth Endothelial Factor-A (VEGFA), supports neuron and endothelial proliferation, and emerged as our molecular target. Combining a mechanical injury approach to induce IVD degeneration and a murine genetic model with the temporal control of VEGFA ablation (UBC-CreERT2; VEGFAfl/fl; Ai9), we investigated the role of VEGFA following injury on structure, function, degeneration, neurovascular development, and pain behavior at acute and chronic timepoints. VEGFA ablation attenuated the neurites and vessels into the IVD. This intervention mitigated the chronic mechanical pain sensitivity and prevented the performance deficits. This is the first study to show a causal relationship between nerves and vessels and pain impairments in the injured IVD. Moreover, VEGFA modulation may be a translatable, disease-modifying therapeutic for chronic low back pain.
Language
English (en)
Chair
Simon Tang