Disc degeneration in the lumbar spine of a small animal model

描述（由申请人提供）： 项目摘要/摘要椎间盘损伤通过创伤，暴露于振动负荷，或机械过载，以及由此产生的椎间盘退变，随着时间的推移，这些侮辱是巨大的问题，影响积极和退伍军人人口。高达44%的美国海湾战争退伍军人在服役后2至5年报告腰痛，发病率比非现役退伍军人高14%，几乎是美国普通人群的两倍。尽管它与疼痛有关，但没有治疗方法可以阻止椎间盘退变的进展。本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。 椎间盘退变是复杂的多因素的。临床研究、动物模型和体外实验已经证明炎性细胞因子在变性中起作用。特别地，炎性细胞因子白细胞介素-12（IL 12）和肿瘤坏死因子1（TNF 1）存在于退化的人椎间盘中。本文提出的体外和体内模型都将阐明进行性变性中涉及的介质和机制，并作为评估两种具有强大治疗潜力的拮抗这些炎性细胞因子IL 1受体拮抗剂（IL 1 RA）和可溶性TNF受体1（sTNFR 1）的药物的平台。我们将测试这些潜在的治疗在以下目的：目的1：研究一种潜在的治疗使用体外NP模型目的2：使用可生物降解的聚合物微球，以提供治疗剂目的3：评估治疗剂在体内模型的椎间盘退变如果成功的话，未来的工作将研究这些代理人在自然发生的退变模型和翻译的大型动物模型。其他潜在的治疗剂可以使用本研究中开发的模型系统开发和测试。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。

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.