Diabetes Induced Disc Degeneration and Prevention

糖尿病引起的椎间盘退变及预防

• 批准号: 9293971
• 负责人: James C. Iatridis
• 金额: $ 53.89万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293971
• 关键词: Address; Advanced Glycosylation End Products; Age; Attenuated; Autopsy; Back Pain; Behavior; Biological Markers; Biological Models; Calcified; Catabolism; Cell physiology; Cells; Clinical; Comorbidity; Data; Development; Diabetes Mellitus; Diet; Epidemic; Fissural; Functional disorder; Future; Genetic; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Health; Human; Hyperglycemia; Hypertrophy; Incidence; Inflammatory; Ingestion; Intervertebral disc structure; Investigation; Knockout Mice; Low Back Pain; Magnetic Resonance Imaging; Measures; Metabolic Diseases; Modeling; Morbidity - disease rate; Mus; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Organ Culture Techniques; Outcome; Pain; Pathologic; Pathway interactions; Patients; Pentosan Polysulfate; Population; Prevention; Pyridoxamine; Regression Analysis; Research; Research Priority; Role; Signal Pathway; Spinal; Spine surgery; Stress; Structure; Testing; Tissues; Vertebral column; Weight maintenance regimen; calcification; crosslink; cytokine; diabetic; economic cost; effective therapy; global health; healing; improved; in vivo; in vivo Model; innovation; insight; intervertebral disk degeneration; minimally invasive; mouse model; non-diabetic; novel; novel therapeutics; nucleus pulposus; prevent; prospective; receptor for advanced glycation endproducts; spine bone structure

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.

项目概要 腰痛是一种全球性健康流行病，通常与椎间盘疼痛 (IVD) 相关 退化 (IDD) 及其日益增加的发病率涉及超过 1000 亿美元的经济损失。研究 IDD 的机制和新疗法是一个主要的研究重点。最近的重要研究提供 有证据表明 2 型糖尿病 (T2DM) 和饮食会增加 IDD 和脊柱手术的疼痛 并发症。建立 T2DM 和 IDD 之间的机制关系可能会带来新的治疗方法 适用于 T2DM 患者和所有 IDD 患者。我们的总体目标是描述并提高对 T2DM 和饮食诱发的 IDD 的机制，并开发安全有效的治疗方法以维持 健康的脊柱并减缓疼痛性 IDD 的进展。很少有研究调查之间的关系 饮食、T2DM 和 IDD 以及我们的初步数据提供了第一个因果关系。我们的数据表明 DM 诱导的 IDD 涉及异位钙化并减少晚期糖化的积累 终产物 (AGE) 和促炎细胞因子可能有助于减轻一些观察到的 IDD。 拟议的研究检验了我们的总体假设，即饮食中摄入 AGEs 和 T2DM 会诱发 由于 AGE 在全身和脊柱组织中的积累，导致病理性和年龄加速 IDD 增加促炎细胞因子、交联以及 IVD 和终板 (EP) 的异位钙化。 我们相信这些异位钙化和 AGE 相关的交联会产生应力集中和脆性 部分导致微骨折、裂隙和纤维化愈合尝试的材料行为 在 DM 和非 DM 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 (RAGE) 测试该假设模型 基因敲除小鼠研究 AGE 和促炎细胞因子在 IDD 和 IDD 中的作用 异位钙化。目标 2 研究 AGE 和高血糖对 IVD 器官的影响，以区分 确定 IDD 和异位钙化的途径时，了解全身和脊柱组织水平的影响之间的关系。 目标 3 将测试 AGE、IDD 与人类 IVD 和细胞中异位钙化之间的直接关系 来自尸检。 该项目意义重大，因为 IDD 带来了巨大的健康负担，并将获得新的见解 关于 IDD 的原因和治疗，以及互补的小鼠和人类研究。方法是 创新是因为与 T2DM 和 IDD 相关的研究非常少，而我们新颖的假设模型 提供了一个可能影响 T2DM 和非 T2DM 患者 IDD 治疗的框架。成功的 该项目的完成将为系统健康与 IDD 之间的关系提供新的见解 对小鼠和人类进行的研究可能会产生与所有 IDD 患者相关的新疗法。