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 下背痛困扰着高达80%的美国人，并占医疗保健和社会成本超过1000亿美元 每年。而椎间盘（IVD）退变和损伤与腰痛密切相关， 疼痛，IVD的病理解剖学特征与腰痛的临床表现之间的因果关系 仍然知之甚少。最近的啮齿类动物的工作表明，轴性腰痛的症状可以概括 腰椎间盘的靶向损伤。损伤引起了IVD的退化后遗症 并产生与轴性腰痛的慢性行为症状相关的神经突浸润。 这一点得到了人体研究的证实，这些研究观察到人类退化IVD中的神经支配增加。 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。感觉神经的增殖与 由神经生长因子（NGF）和血管内皮生长因子A（VEGFA）调节。神经生长因子是关键的 VEGFA在神经元的自我平衡功能中起重要作用，而VEGFA在自发性神经突延伸中起关键作用， 除了引发血管生成之外，还可以促进结缔组织中的树突状生长。退化和损伤的IVD 细胞表达VEGFa作为炎症级联反应的一部分，但VEGFA对炎症细胞的机制作用， 尚未研究IVD中的新神经支配和随后的下背痛行为。 这个提议的中心假设是VEGFA的消融减弱了神经突的生长 血管化进入受伤的IVD并减轻随后的腰痛症状。我们将 通过以下具体目标调查假设：具体目标1：确定删除是否 损伤后2天的VEGFA阻止了IVD神经支配和血管形成，并且腰痛症状3- 以及目标性损伤后12周。具体目标2：确定是否删除VEGFA 6周 损伤后减慢、阻止或逆转IVD神经支配和血管形成，以及腰痛症状12- 几周后，有针对性的伤害。 对VEGFA在改变病理解剖学中的作用的机制性理解将为研究VEGFA在病理解剖学中的作用铺平道路。 下背痛的疾病修饰疗法。抗VEGF疗法的易于递送使其成为一种有吸引力的 VEGFA是患病IVD的候选药物，并且抗VEGFA已经被批准用于治疗黄斑病变。 退化和癌症。这里的概念验证工作也将为未来的 通过利用CreERT 2的组织特异性驱动因子研究VEGFA的来源; VEGF串扰 椎间盘，内皮细胞和感觉神经元之间的关系;并利用这些慢性下背部 疼痛机制作为潜在的治疗方法。