Diabetes Induced Disc Degeneration and Prevention

项目总结 下腰痛是一种全球性的健康流行病，通常与腰椎间盘痛(IVD)有关。 退化性疾病(IDD)及其不断增加的发病率涉及超过1000亿美元的经济损失。研究…… IDD的机制和新的治疗方法是一个主要的研究重点。最近的重要研究提供了 有证据表明，2型糖尿病(T2 DM)和饮食会增加痛苦的IDD和脊柱手术 并发症。在T2 DM和IDD之间建立机制关系可能导致新的治疗方法 适用于T2 DM患者和所有IDD患者。我们的广泛目标是描述和改善对 2型糖尿病和饮食诱导的IDD的机制，并开发安全有效的治疗方法来维持 健康的脊椎和延缓疼痛的IDD的进展。很少有研究调查两者之间的关系 饮食、T2 DM和IDD以及我们的初步数据提供了第一个因果关系。我们的数据显示 糖尿病引起的IDD涉及异位钙化和减少晚期糖基化的积累 终末产物(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T2 DM会导致 全身性和脊椎组织中AGE积聚所致的病理性和老年性加速IDD 与促炎细胞因子增加、交联化以及IVD和终板(EP)的异位钙化有关。 我们认为这些异位钙化和年龄相关的交联会造成应力集中和脆性 材料行为对微骨折、裂缝和纤维性愈合尝试负有部分责任 通常在糖尿病和非糖尿病患者中观察到痛苦的人类IDD。 目标1将使用T2 DM、高年龄摄入量和年龄受体(RAGE)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研究年龄和高血糖对IVD器官的影响，以区分 全身和脊柱组织水平效应之间的关系，同时确定IDD和异位钙化的途径。 AIM 3将测试AGE、IDD和人类IVD和细胞异位钙化之间的直接关系 从尸检中发现的。 这个项目意义重大，因为IDD带来了巨大的健康负担，将获得新的见解 关于碘缺乏病的病因和治疗，以及补充的小鼠和人体研究。方法是 创新是因为关于T2 DM和IDD的研究非常少，而且我们的新假设模型 提供了一个框架，可能会影响T2 DM和非T2 DM患者的IDD治疗。成功 该项目的完成将为系统健康和IDD之间的关系提供新的见解 小鼠和人类的研究可能导致与所有IDD患者相关的新治疗方法。

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.