Diabetes Induced Disc Degeneration and Prevention

项目摘要 下背痛是一种全球流行病，通常与椎间盘疼痛（IVD）相关。 变性（IDD）及其发病率的增加涉及超过1000亿美元的经济成本。研究 IDD的机制和新的治疗方法是一个主要的研究优先事项。最近的重要研究提供了 2型糖尿病（T2DM）和饮食可增加疼痛的IDD和脊柱手术的证据 并发症建立T2DM和IDD之间的机制关系可能会导致新的治疗方法 T2DM和所有IDD患者。我们的主要目标是描述和提高对 T2DM和饮食诱导的IDD的机制，并开发安全有效的治疗方法，以维持 健康的脊柱和减缓疼痛的IDD的进展。很少有研究调查 饮食、2型糖尿病和碘缺乏病，我们的初步数据提供了第一个因果关系。我们的数据表明 DM诱导的IDD涉及异位钙化， 终产物（AGEs）和促炎细胞因子可能有助于减轻一些观察到的IDD。 拟议的研究验证了我们的总体假设，即饮食摄入AGEs和T2DM诱导 病理性和年龄加速性IDD，由于AGE全身性和脊髓组织中的蓄积， 增加促炎细胞因子、交联和IVD和终板（EP）的异位钙化。 我们认为这些异位钙化和AGE相关的交联造成应力集中和脆性。 材料行为，部分负责微骨折，裂缝，和纤维化愈合尝试 在糖尿病和非糖尿病患者的疼痛性IDD中常见。 目标1将使用T2DM、高AGE摄入和AGE受体（Receptor for AGE，RGE）来测试这一假设模型。 基因敲除小鼠研究AGEs和促炎细胞因子在IDD和 异位钙化目的2探讨AGE和高血糖对IVD器官的影响， 在识别IDD和异位钙化的途径时，系统和脊柱组织水平效应之间的关系。 目的3将测试AGEs，IDD和人类IVD和细胞中异位钙化之间的直接关系 尸体解剖。 该项目意义重大，因为缺碘症造成巨大的健康负担， 关于缺碘症的病因和治疗，以及补充的小鼠和人类研究。该方法是 创新性，因为有关T2DM和IDD的研究非常少，我们的新假设模型 提供了一个可能影响T2DM和非T2DM患者IDD治疗的框架。成功 这一项目的完成将为系统健康与缺碘症之间的关系提供新的见解， 小鼠和人类的研究，可能会导致新的治疗相关的所有IDD患者。

PROJECT SUMMARY Low back pain is a global health epidemic commonly associated with painful intervertebral disc (IVD) degeneration (IDD) and its increasing incidence involves economic costs over $100 billion. Research into mechanisms and novel treatments for IDD is a major research priority. Important recent studies provide evidence that type 2 diabetes mellitus (T2DM) and diet can increase painful IDD and spine surgery complications. Establishing a mechanistic relationship between T2DM and IDD may result in novel therapies for T2DM patients and all IDD patients. Our broad goal is to characterize and improve understanding of mechanisms for T2DM- and diet-induced IDD and to develop safe and effective treatments to maintain a healthy spine and to slow the progression of painful IDD. Little research investigates relationships between diet, T2DM, and IDD and our preliminary data provide among the first causal relationships. Our data suggest that DM-induced IDD involves ectopic calcifications and that reducing the accumulation of advanced glycation endproducts (AGEs) and pro-inflammatory cytokines may help mitigate some of the observed IDD. The proposed studies test our overall hypothesis that dietary ingestion of AGEs and T2DM induces pathological and age-accelerated IDD due to AGE accumulation systemically and also in spinal tissues leading to increased pro-inflammatory cytokines, crosslinking, and ectopic calcifications of IVDs and endplates (EPs). We believe these ectopic calcifications and AGE associated crosslinks create stress concentrations and brittle material behaviors that are partially responsible for the microfractures, fissures, and fibrotic healing attempts commonly observed in painful human IDD in both DM and non-DM patients. Aim 1 will test this hypothetical model using T2DM, high-AGE ingestion, and Receptor for AGE (RAGE) knockout mice to investigate the roles of AGEs and pro-inflammatory cytokines in contributing to IDD and ectopic calcifications. Aim 2 investigates AGE and hyperglycemia effects on IVD organs in order to distinguish between systemic and spine tissue level effects while identifying pathways for IDD and ectopic calcification. Aim 3 will test for direct relationships between AGEs, IDD and ectopic calcifications in human IVDs and cells from autopsy. This project is significant because of the tremendous health burden of IDD, the new insights that will be gained regarding causes and treatment of IDD, and the complementary mouse and human studies. The approach is innovative because there are remarkably few studies relating T2DM and IDD, and our novel hypothetical model provides a framework that may impact IDD treatments for both T2DM and non-T2DM patients. Successful completion of this project will provide new insights into the relationships between systemic health and IDD in mice and humans with investigations that may result in novel treatments relevant to all IDD patients.