Inhibition of TNF-alpha Signaling to Reduce Intervertebral Disc Inflammation

抑制 TNF-α 信号传导以减少椎间盘炎症

• 批准号: 10301274
• 负责人: YEJIA ZHANG
• 金额: $ 21.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301274
• 关键词: Anti-Tumor Necrosis Factor Therapy; Antibodies; Applications Grants; Back Pain; CXCL1 gene; Categories; Cell Death; Clinical; Control Groups; Cytokine Gene; Cytoplasmic Protein; Data; Dimethyl Sulfoxide; Disease; Drug Delivery Systems; Equilibrium; Family; Family member; Gene Expression; Gene Family; Genes; Genetic; Goals; Histologic; IL6 gene; Immunologist; Infiltration; Inflammation; Injections; Injury; Intervertebral disc structure; Knock-out; Knockout Mice; Lead; Mediating; Methods; Modification; Molecular; Molecular Conformation; Mus; Mutant Strains Mice; Natural regeneration; Neck Pain; Needles; Operative Surgical Procedures; Oral; Pain; Patients; Penetration; Pharmaceutical Preparations; Protein Family; Proteins; Puncture procedure; Recording of previous events; Research; Scientist; Signal Transduction; Signaling Protein; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Tail; Testing; Therapeutic; Wild Type Mouse; burden of illness; carcinogenesis; chronic back pain; cost; cytokine; design; effective therapy; falls; inflammatory marker; inhibitor/antagonist; injured; intervertebral disk degeneration; macrophage; member; novel; pain reduction; response to injury; small molecule; small molecule inhibitor; spinal disk injury; tool; tumor necrosis factor-alpha inhibitor

Abstract Chronic back pain related to intervertebral disc (IVD) degeneration is a significant problem, costing billions in the U.S. alone. Our proposal will explore new aspects of the factors that lead to disc degeneration and inflammation, thus accelerating research on IVD degeneration and related back pain. The TNF-α-induced protein-8 (TNFAIP8, known as TIPE) family consists of four members (TNFAIP8 and TIPE1-3). They are novel cytoplasmic proteins recently found to be key factors regulating inflammation. Our preliminary data have shown that TNFAIP8 family proteins regulate macrophage infiltration into the injured IVD. The premise of our proposal is that TNFAIP8 family members may be key regulators in IVD inflammation, and that a novel small molecule inhibitor of tumor necrosis factor receptor (TNFR)-1 could represent a therapeutic tool to reduce inflammation. In Aim 1, we hypothesize that genetic inactivation of TNFAIP8/TIPE2 results in reduced inflammation in the injured mouse tail IVD. We will determine if genetic inactivation of TNFAIP8/TIPE2 will ameliorate IVD inflammation and degeneration. We have acquired and are currently maintaining colonies of mutant mice lacking two members of the TNFAIP8 family (TNFAIP8-/-, TIPE2-/-, and TNFAIP8/TIPE2 double knockout). Mouse tail IVDs will be challenged with a needle puncture injury. Changes in macrophage infiltration and cytokine gene expression post-injury will be compared among the mutant mice and with their wild type littermate controls. In Aim 2, we further hypothesize that a novel small molecule inhibitor of TNFR1 (SGT11) could represent a therapeutic tool to reduce inflammation. Small molecules are especially attractive since they could be modified for oral drug delivery. SGT11 has been shown to inhibit inflammation by changing the conformation of TNFR1. Unlike current anti-TNF therapy that inhibits both TNFR1 and TNFR2 activation, SGT11 inhibits TNFR1 but not TNFR2. If successful, this will be the first small molecule to modulate IVD inflammation. We will determine if SGT11 could ameliorate IVD inflammation and reduce TNFAIP8/TIPE2 expression in the wild-type mouse. Mouse tail IVDs will be punctured with a needle, with or without SGT11 treatment. Changes in macrophage infiltration, cytokine and TNFAIP8 family gene expression in the IVD will be compared between SGT11-treated and control groups. The proposed exploratory study breaks ground toward a novel direction since modulating TNF-TNFAIP8 axia with genetic methods and small molecule inhibitors has not been previously studied in the IVD. Discovery of drugs that modulate IVD inflammation would result in a paradigm shift from current invasive surgeries on late stage disease to early noninvasive therapies, thus benefiting patients.

摘要 与椎间盘退变相关的慢性背痛是一个重大问题， 仅在美国就有数十亿美元。我们的提案将探索导致椎间盘退变的因素的新方面 以及炎症，从而加速了对IVD变性和相关背痛的研究。 肿瘤坏死因子-α诱导蛋白-8(TNFAIP8)家族由四个成员组成(TNFAIP8和TIPE TIPE1-3)。它们是最近发现的新的细胞质蛋白，是调节炎症的关键因素。我们的 初步数据表明，TNFAIP8家族蛋白调节巨噬细胞对受损的IVD的渗透。 我们建议的前提是TNFAIP8家族成员可能是IVD炎症的关键调节因子，并且 一种新的肿瘤坏死因子受体(TNFR)-1小分子抑制物可能代表一种治疗 消炎的工具。 在目标1中，我们假设TNFAIP8/TIPE2的基因失活导致脑组织炎症减轻 损伤的小鼠尾巴IVD。我们将确定TNFAIP8/TIPE2的基因失活是否会改善IVD 发炎和变性。我们已经获得并正在维持缺乏突变小鼠的群体 TNFAIP8家族的两个成员(TNFAIP8-/-、TIPE2-/-和TNFAIP8/TIPE2双基因敲除)。老鼠尾巴 静脉注射器将受到针刺损伤的挑战。巨噬细胞浸润和细胞因子基因的变化 将在突变小鼠和它们的野生型小鼠对照中比较损伤后的表达。 在目标2中，我们进一步假设一种新的TNFR1小分子抑制剂(SGT11)可以 是一种减少炎症的治疗工具。小分子特别吸引人，因为它们可以 被改装为口服给药。SGT11已被证明通过改变构象来抑制炎症 肿瘤坏死因子受体1的表达。与目前同时抑制TNFR1和TNFR2激活的抗肿瘤坏死因子治疗不同，SGT11抑制 TNFR1而不是TNFR2。如果成功，这将是第一个调节IVD炎症的小分子。我们会 确定SGT11是否可以减轻IVD炎症并降低野生型TNFAIP8/TIPE2的表达 老鼠。无论有没有SGT11治疗，都会用针刺穿小鼠的尾部静脉畸形。中的更改 巨噬细胞浸润、细胞因子和TNFAIP8家族基因在IVD中的表达 SGT11治疗组和对照组。 自从调节肿瘤坏死因子-TNFAIP8以来，这项拟议的探索性研究朝着一个新的方向取得了进展 AXIA与遗传方法和小分子抑制剂在IVD中以前没有研究过。发现 调整IVD炎症的药物将导致从目前的侵入性手术到晚期的范式转变 将疾病分期到早期非侵入性治疗，从而使患者受益。