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

基本信息

批准号：
10448429
负责人：
YEJIA ZHANG
金额：
$ 17.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448429
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 effective therapy falls inflammatory marker inhibitor injured intervertebral disk degeneration macrophage member novel pain reduction rational design response to injury small molecule small molecule inhibitor spinal disk injury tool tumor necrosis factor-alpha inhibitor

项目摘要

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.

抽象的与椎间盘（IVD）退变相关的慢性背痛是一个严重的问题，成本高昂仅在美国就有数十亿美元。我们的提案将探讨导致椎间盘退变的因素的新方面。和炎症，从而加速 IVD 退化和相关背痛的研究。 TNF-α诱导蛋白8（TNFAIP8，称为TIPE）家族由四个成员组成（TNFAIP8和 TIPE1-3)。它们是最近发现的新型细胞质蛋白，是调节炎症的关键因素。初步数据表明，TNFAIP8 家族蛋白调节巨噬细胞浸润到受损的 IVD 中。我们提议的前提是TNFAIP8家族成员可能是IVD炎症的关键调节因子，并且肿瘤坏死因子受体 (TNFR)-1 的新型小分子抑制剂可能代表一种治疗方法减少炎症的工具。在目标 1 中，我们勇敢地承认 TNFAIP8/TIPE2 的基因失活可减少炎症我们将确定 TNFAIP8/TIPE2 的基因失活是否会改善 IVD。我们已经获得并正在维持缺乏炎症和退化的突变小鼠群体。 TNFAIP8 家族的两个成员（TNFAIP8-/-、TIPE2-/- 和 TNFAIP8/TIPE2 双敲除小鼠尾部）。 IVD 将面临巨噬细胞浸润和细胞因子基因变化的挑战。将比较突变小鼠及其野生型同窝对照小鼠损伤后的表达。在目标 2 中，我们进一步追求一种新型的 TNFR1 小分子抑制剂（SGT11）可以代表一种减少炎症的治疗工具特别有吸引力，因为它们可以 SGT11 已被证明可以通过改变构象来抑制炎症。与目前抑制 TNFR1 和 TNFR2 激活的抗 TNF 疗法不同，SGT11 抑制 TNFR1 的激活。 TNFR1 而不是 TNFR2 如果成功，这将是第一个调节 IVD 炎症的小分子。确定 SGT11 是否可以改善 IVD 炎症并降低野生型中 TNFAIP8/TIPE2 的表达小鼠尾部 IVD 将用针刺穿，无论是否经过 SGT11 处理。 IVD 中的巨噬细胞浸润、细胞因子和 TNFAIP8 家族基因表达将进行比较 SGT11 处理组和对照组。自调节 TNF-TNFAIP8 以来，拟议的探索性研究朝着一个新的方向取得了突破 IVD Discovery 之前尚未研究过用遗传方法和小分子抑制剂治疗轴心病。调节 IVD 炎症的药物将导致当前侵入性手术的范式转变将疾病分期到早期无创治疗，从而使患者受益。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Therapeutic potential of TNFα inhibitors in chronic inflammatory disorders: Past and future.

TNFα 抑制剂在慢性炎症性疾病中的治疗潜力：过去和未来。

DOI：
发表时间：
2021-01
期刊：
影响因子：
6.8
作者：
Zhang, Hongtao;Shi, Nelson;Diao, Zhuo;Chen, Youhai;Zhang, Yejia
通讯作者：
Zhang, Yejia

TNFAIP8 family gene expressions in the mouse tail intervertebral disc injury model.

小鼠尾椎间盘损伤模型中TNFAIP8家族基因的表达。

DOI：
发表时间：
2020-06
期刊：
影响因子：
3.7
作者：
Tian, Zuozhen;Shofer, Frances S;Yao, Lutian;Sun, Honghong;Zhang, Hongtao;Qin, Ling;Chen, Youhai H;Zhang, Yejia
通讯作者：
Zhang, Yejia

Biomarkers in the Degenerative Human Intervertebral Disc Tissue and Blood.

退行性人类椎间盘组织和血液中的生物标志物。

DOI：
发表时间：
2022-10-01
期刊：
影响因子：
3
作者：
Zhang, Yejia;Yao, Lutian;Robinson, Keith M;Dillingham, Timothy R
通讯作者：
Dillingham, Timothy R

A microwell-based impedance sensor on an insertable microneedle for real-time in vivo cytokine detection.

可插入微针上基于微孔的阻抗传感器，用于实时体内细胞因子检测。

DOI：
发表时间：
2021
期刊：
影响因子：
7.9
作者：
Song, Naixin;Xie, Pengfei;Shen, Wen;Oh, Hanju;Zhang, Yejia;Vitale, Flavia;Javanmard, Mehdi;Allen, Mark G
通讯作者：
Allen, Mark G

Tnfa , Il6 , Cxcl1 , and Adam8 Genes Are the Early Markers After Mouse Tail Intervertebral Disc Injury.

Tnfa、Il6、Cxcl1 和 Adam8 基因是小鼠尾椎间盘损伤后的早期标志物。

DOI：
发表时间：
2023-12-01
期刊：
影响因子：
3
作者：
Lu, Jiawei;Tian, Zuozhen;Shofer, Frances S;Yao, Lutian;Sandroni, Alec Z;Sun, Honghong;Qin, Ling;Zhang, Yejia
通讯作者：
Zhang, Yejia