Diabetes Induced Disc Degeneration and Prevention

糖尿病引起的椎间盘退变及预防

• 批准号: 9185665
• 负责人: James C. Iatridis
• 金额: $ 55.63万
• 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/9185665
• 关键词: Address; Advanced Glycosylation End Products; Attenuated; Autopsy; Back Pain; Behavior; Biological Markers; Biological Models; Catabolism; Cell physiology; Cells; Clinical; Comorbidity; Data; Development; Diabetes Mellitus; Diet; Epidemic; Functional disorder; Future; Genetic; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Healed; Health; Histocompatibility Testing; 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; 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 patient; 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; pathological aging; 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.

项目摘要 腰痛是一种全球健康流行病，通常与椎间盘疼痛有关（IVD） 退化（IDD）及其发病率的增加涉及经济成本超过1000亿美元。研究 IDD的机制和新型治疗方法是主要的研究重点。重要的最近研究提供 2型糖尿病（T2DM）和饮食可以增加疼痛的IDD和脊柱手术的证据 并发症。建立T2DM和IDD之间的机械关系可能会导致新的疗法 适用于T2DM患者和所有IDD患者。我们的广泛目标是表征和提高对 T2DM和饮食引起的IDD的机制，并开发安全有效的治疗方法以维持 健康的脊柱并减慢疼痛IDD的进展。很少的研究调查了 饮食，T2DM和IDD以及我们的初步数据提供了第一个因果关系。我们的数据暗示 DM诱导的IDD涉及异位钙化，并减少高级糖基化的积累 最终产物（年龄）和促炎细胞因子可能有助于减轻某些观察到的IDD。 拟议的研究检验了我们的总体假设，即饮食摄入年龄和T2DM会诱导 病理学和年龄加速IDD，由于年龄的积累，在脊柱组织中累积 为了增加IVD和终结（EPS）的促炎细胞因子，交联和异位钙化。 我们认为这些异位钙化和与年龄相关的交联会产生应力浓度和脆性 对微裂缝，裂缝和纤维化愈合尝试部分负责的物质行为 在DM和非DM患者中，通常在疼痛的人IDD中观察到。 AIM 1将使用T2DM，高年龄摄入和年龄的受体（RAGE）测试该假设模型 敲除小鼠研究年龄和促炎细胞因子在促成IDD和促疾病的作用 异位钙化。 AIM 2研究年龄和高血糖对IVD器官的影响，以区分 在识别IDD和异位钙化途径的同时，在全身和脊柱组织水平的效果之间。 AIM 3将测试人类IVD和细胞中年龄，IDD和异位钙化之间的直接关系 从尸检。 由于IDD的巨大健康负担，该项目很重要，将获得的新见解 关于IDD的原因和治疗，以及互补的小鼠和人类研究。方法是 创新的是因为很少有与T2DM和IDD有关的研究，以及我们的新型假设模型 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。 小鼠和人类进行的研究可能导致与所有IDD患者有关的新型治疗。