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Disc degeneration in the lumbar spine of a small animal model

小动物腰椎间盘退变模型

基本信息

批准号：
8894384
负责人：
Nader M Hebela
金额：
--
依托单位：
PHILADELPHIA VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-10-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8894384
关键词：
Affect Animal Model Back Pain Biochemical Biochemistry Biological Biological Models Bolus Infusion Canis familiaris Cattle Cell Death Cells Clinical Research Collagen Collagen Gene Complex Down-Regulation Encapsulated Exposure to Future GAG Gene Gene Expression General Population Genes Goat Gulf War Histology Human In Vitro Incidence Inflammatory Injection of therapeutic agent Interleukin-1 Receptors Interleukin-1 beta Interleukin-12 Interstitial Collagenase Link Low Back Pain Lumbar Disc Degenerative Disorder Measures Mechanics Mediator of activation protein Microspheres Military Personnel Modeling Needles Pain Pathogenesis Physiological Play Population Proteins Puncture procedure Rattus Reporting Role Sand Rats Sepharose Services Sheep Simulate Structure Testing Therapeutic Therapeutic Agents Time Transforming Growth Factor beta Trauma Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Up-Regulation Vertebral column Veterans Work abstracting aggrecan cytokine dosage in vivo in vivo Model inhibitor/antagonist intervertebral disk degeneration nucleus pulposus research study response spinal disk injury stem three-dimensional modeling

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract Intervertebral disc injury through trauma, exposure to vibrational loading, or mechanical overload, and the resulting disc degeneration in response to these insults over time are tremendous problems affecting the active and veteran military population. As high as 44% of U.S. Gulf War veterans report low back pain only 2 to 5 years following service, an incidence rate 14% higher than non-active duty veterans and a rate nearly twice that of the general US population. Despite its link with pain, there are no treatments that stop the progression of disc degeneration. The objective of this proposal is to investigate the mechanisms of and potential restorative therapies for intervertebral disc degeneration utilizing an in vitro nucleus pulposus (NP) model and an in vivo small animal model. Disc degeneration is complex and multifactorial. Clinical studies, animal models, and in vitro experiments have demonstrated inflammatory cytokines play a role in degeneration. In particular, inflammatory cytokines interleukin-12 (IL12) and tumor necrosis factor 1 (TNF1) are present in degenerated human discs. Both the in vitro and in vivo models proposed here will elucidate the mediators and mechanisms involved in progressive degeneration and act as platforms to evaluate two agents that counteract these inflammatory cytokines, IL1 receptor antagonist (IL1RA) and soluble TNF receptor 1(sTNFR1), which have strong therapeutic potential. We will test these potential therapies in the following Aims: Aim 1: Investigate a potential therapy using an in vitro NP model Aim 2: Use biodegradable polymeric microspheres to deliver therapeutic agents Aim 3: Evaluate therapeutic agents in an in vivo model of disc degeneration If successful, future work will study these agents in naturally occurring models of degeneration and in translational large animal models. Other potential therapeutic agents can be developed and tested using the model systems developed in this study. This work will impact treatment for a significant proportion of the population, including military active duty and veteran, who suffer with disc degeneration and back pain.

描述（由申请人提供）：项目摘要/摘要外伤、振动负荷或机械超负荷造成的椎间盘损伤，以及随着时间的推移这些损伤而导致的椎间盘退变，是影响现役和退伍军人的巨大问题。高达 44% 的美国海湾战争退伍军人在服役后仅 2 至 5 年就出现腰痛，发病率比非现役退伍军人高 14%，几乎是美国普通民众的两倍。尽管它与疼痛有关，但没有任何治疗方法可以阻止椎间盘退变的进展。该提案的目的是利用体外髓核（NP）模型和体内小动物模型研究椎间盘退变的机制和潜在的恢复疗法。椎间盘退变是复杂且多因素的。临床研究、动物模型和体外实验已证明炎症细胞因子在变性中发挥作用。特别是，退变的人类椎间盘中存在炎性细胞因子白介素 12 (IL12) 和肿瘤坏死因子 1 (TNF1)。这里提出的体外和体内模型都将阐明参与进行性变性的介质和机制，并作为评估两种对抗这些炎症细胞因子的药物的平台，即IL1受体拮抗剂（IL1RA）和可溶性TNF受体1（sTNFR1），这两种药物具有强大的治疗潜力。我们将在以下目标中测试这些潜在疗法：目标 1：使用体外 NP 模型研究潜在疗法目标 2：使用可生物降解的聚合物微球来递送治疗剂目标 3：在椎间盘退变的体内模型中评估治疗剂如果成功，未来的工作将在自然发生的退变模型和转化大型动物模型中研究这些药物。使用本研究中开发的模型系统可以开发和测试其他潜在的治疗剂。这项工作将影响很大一部分人口的治疗，包括现役军人和退伍军人，他们患有椎间盘退变和背痛。