The Role of VEGF in the Development of Low Back Pain Following IVD Injury

项目摘要 高达80%的美国人患有腰痛，造成了超过1000亿美元的医疗和社会成本 每年一次。而腰间盘(IVD)的退变和损伤与腰背有很强的相关性 疼痛，下腰痛的病理解剖特征与临床表现之间的关系 人们对此仍然知之甚少。最近的啮齿动物研究表明，轴性下腰痛的症状可以概括出来 由腰间盘的靶向损伤。这一损伤引起了IVD的退行性后遗症 并产生与轴性下腰痛的慢性行为症状有关的轴突渗透。 这一点得到了人类研究的证实，这些研究观察到人类退行性IVD的神经支配增加。 因此，了解驱动IVD神经支配的分子事件可能会为治疗提供见解 在过渡到慢性LBP症状之前的机会。感觉神经的增殖紧密地 受神经生长因子(NGF)和血管内皮生长A(VEGFA)调节。NGF提供关键服务 神经元的动态平衡功能，而VEGFA在自发的轴突延伸和 除了启动血管生成外，结缔组织中的树突状突起。退行性和损伤性IVD 细胞表达VEGFA是炎性级联反应的一部分，但VEGFA的作用机制不同。 IVD中的新神经支配和随后的下腰痛行为尚未被研究。 这一提议的中心假设是，消融VEGFA可以减弱轴突生长 和血管进入受伤的IVD，并缓解随之而来的腰痛症状。我们会 通过以下具体目标调查假设：具体目标1：确定是否删除 伤后2天应用VEGFA可预防IVD的神经支配和血管形成，以及腰痛症状。 以及靶向损伤后的12周。具体目标2：确定是否删除VEGFA 6周 受伤后减缓、阻止或逆转IVD神经支配和血管形成，以及下腰痛症状 在一次定向受伤后的几周内。 从机制上理解VEGFA在改变病理解剖结构中的作用将为 下腰痛的疾病修正疗法。易于传递的抗血管内皮生长因子疗法使其成为一种有吸引力的 疾病IVD的候选药物和抗VEGFA已被批准用于治疗黄斑 人类的退化和癌症。这里的概念验证工作也将为未来的工作奠定基础 利用CRERT2的组织特异性驱动因素研究VEGFA的来源；血管内皮生长因子串扰 在椎间盘、内皮细胞和感觉神经元之间；并利用这些慢性下腰 疼痛机制作为潜在的治疗方法。

Project Abstract Low back pain afflicts up to 80% of Americans and accounts for over $100 billion in healthcare and social costs annually. While intervertebral disc (IVD) degeneration and injury have been strongly associated with low back pain, the causation between pathoanatomical features of the IVD and clinical presentation of low back pain remains poorly understood. Recent rodent work show that axial low back pain symptoms can be recapitulated by the targeted injury of the lumbar intervertebral disc. The injury evokes a degenerative sequala in the IVD and produces neurite infiltration that are associated with chronic behavioral symptoms of axial low back pain. This is corroborated by human studies that observed increased innervation in degenerated IVD from humans. Thus, understanding the molecular events that drives IVD innervation may provide insights to therapeutic opportunities prior to the transition to chronic LBP symptoms. The proliferation of sensory nerves is tightly regulated by Nerve Growth Factor (NGF) and Vascular Endothelial Growth A (VEGFA). NGF serves critical homeostatic functions in neurons, while VEGFA plays a crucial role in spontaneous neurite extension and dendritic outgrowth in connective tissues, in addition to initiating angiogenesis. Degenerate and injured IVD cells express VEGFa as a part of the inflammatory cascade, but the mechanistic effects of VEGFA on neoinnervation in the IVD and subsequent low back pain behavior have not been investigated. The central hypothesis of this proposal is that the ablation of VEGFA attenuates neurite growth and vascularization into the injured IVD and alleviates ensuing low back pain symptoms. We will investigate the hypotheses through the following specific aims: Specific Aim 1: Determine whether the deletion of VEGFA 2-days after injury prevents IVD innervation and vascularization, and low back pain symptoms 3- and 12- weeks following a targeted injury. Specific Aim 2: Determine whether the deletion of VEGFA 6-weeks after injury slows, arrests, or reverses IVD innervation and vascularization, and low back pain symptoms 12- weeks following a targeted injury. The mechanistic understanding of VEGFA’s role in modifying the pathoanatomy will pave the way as a disease modifying therapy for low back pain. The ease for delivery anti-VEGF therapies makes it an attractive candidate for the diseased IVD, and anti-VEGFA has already been approved for the treatment of macular degeneration and cancer in humans. The proof-of-concept work here will also lay the foundation for future studies to investigate the source of VEGFA by utilizing tissue-specific drivers of CreERT2; the VEGF crosstalk between intervertebral disc, endothelial cells, and sensory neurons; and leveraging these chronic low back pain mechanisms as potential therapies.