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

VEGF 在 IVD 损伤后腰痛发展中的作用

• 批准号: 10668079
• 负责人: Munish Gupta
• 金额: $ 17.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668079
• 关键词: Abate; Ablation; Adult; Afferent Neurons; Alleles; American; Analgesics; Anatomy; Animals; Attenuated; Behavioral Symptoms; Blood Vessels; Cells; Chronic; Chronic low back pain; Clinical; Connective Tissue; Data; Development; Disease; Embryo; Endothelial Cells; Enterobacteria phage P1 Cre recombinase; Etiology; Event; Excision; Experimental Designs; Exposure to; Foundations; Future; Goals; Growth; Healthcare; Human; Immunofluorescence Immunologic; Infiltration; Inflammatory; Inflammatory Response; Injury; Intervention; Intervertebral disc structure; Laboratories; Locomotion; Low Back Pain; Macular degeneration; Malignant Neoplasms; Molecular; Monitor; Mus; Nerve; Nerve Growth Factors; Neurites; Neurons; Operative Surgical Procedures; Pain; Pathologic; Performance; Play; Prevention; Proliferating; Retroperitoneal Space; Rodent; Rodent Model; Role; Source; Spinal Ganglia; Structure; Symptoms; Tamoxifen; Therapeutic; Tissues; Ubiquitin; VEGFA gene; Vascular Endothelial Growth Factors; Vascularization; Vegf inhibition; Work; afferent nerve; angiogenesis; behavior test; bevacizumab; contrast enhanced; cost; improved; in vivo; inducible Cre; innovation; insight; intervertebral disk degeneration; microCT; mouse model; neovascularization; nerve supply; neurite growth; pain behavior; pain symptom; persistent symptom; postnatal; prevent; social; spinal disk injury; therapy development

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.

项目摘要 高达 80% 的美国人患有腰痛，造成的医疗保健和社会成本超过 1000 亿美元 椎间盘（IVD）退变和损伤与腰背密切相关。 疼痛、IVD 病理解剖学特征与腰痛临床表现之间的因果关系 最近的啮齿动物研究表明，轴性腰痛症状可以重现。 腰椎间盘的针对性损伤引起 IVD 中的退行性后遗症。 并产生与轴性腰痛的慢性行为症状相关的神经突浸润。 人类研究证实了这一点，研究观察到人类退化 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为治疗提供见解。 转变为慢性腰痛症状之前的机会 感觉神经的增殖紧密。 神经生长因子 (NGF) 和血管内皮生长 A (VEGFA) 的调节至关重要。 VEGFA 在神经元中发挥稳态功能，而 VEGFA 在自发神经突延伸和 结缔组织中的树突生长，以及启动血管生成退化和受损的 IVD。 细胞表达 VEGFa 作为炎症级联反应的一部分，但 VEGFA 的机制作用 IVD 中的新神经支配和随后的腰痛行为尚未得到研究。 该提案的中心假设是 VEGFA 的消融会减弱神经突的生长 和血管化进入受伤的 IVD 并减轻随后的腰痛症状。 通过以下具体目标来调查假设： 具体目标 1：确定是否删除 损伤后 2 天添加 VEGFA 可防止 IVD 神经支配和血管化以及腰痛症状 3- 目标损伤后 12 周 具体目标 2：确定 6 周后是否删除 VEGFA。 受伤后减缓、停止或逆转 IVD 神经支配和血管化以及腰痛症状 12- 有针对性的伤害几周后。 对 VEGFA 在改变病理解剖学中的作用的机制理解将为作为 治疗腰痛的疾病修饰疗法易于提供抗 VEGF 疗法，使其成为一种有吸引力的疗法。 抗 VEGFA 药物已被批准用于治疗黄斑病变 这里的概念验证工作也将为未来奠定基础。 利用 CreERT2 的组织特异性驱动因素调查 VEGFA 来源的研究； 椎间盘、内皮细胞和感觉神经元之间的作用，并利用这些慢性腰痛； 疼痛机制作为潜在的治疗方法。