The role of physiologic and pathologic AGEs on RAGE signaling in IVD degeneration

项目摘要 腰椎间盘退行性变(IVD)是导致背痛的主要因素，这是一种流行病， 在美国有数十亿美元。IVD由富含蛋白多糖(PG)的髓核(NP)包围 由胶原纤维环(AF)共同提供支持和传递复杂的负荷。IVD 退化级联包括生物、生化和结构变化的多因素进展。 这会导致圆盘结构的坍塌并损害机械功能。尽管它意义重大 对公众健康的影响，椎间盘退变的病理生理学仍不清楚。 晚期糖基化终末产物(AGEs)的积累与衰老和 糖尿病。年龄的增加也与IVD的退变有关。年代相传 非酶糖基化，胞外糖类与氨基酸进行美拉德重排，以 变成蛋白质加合物和交联物。已知AGEs会损害基质蛋白的机械功能。 除基质修饰外，AGEs还可激活晚期糖基化终产物的细胞受体 (RAGE)，并且RAGE信号使免疫和炎症反应持续存在。因为IVD是无血管的 且组织重塑程度相对较低，IVD组织易积聚年龄。尽管如此 据观察，AGEs或RAGE信号在IVD退变中是否起因果作用尚不清楚。 在这个R01应用中，我们将确定AGEs和RAGE介导的事件作为疾病机制 治疗IVD退行性疾病。具体来说，我们将确定AGEs在改变IVD结构和功能方面的作用，并 定义愤怒信号在AGEs介导的退行性变中的必要性。如果我们的假设得到支持，这 将为减轻退化的级联反应提供假定的靶点。体内和体外的结合-- 体外方法将使我们能够仔细剖析来自组织的高年龄负荷的全身影响- 年龄的具体影响。我们还将进一步发展体内对比增强显微CT。 将椎间盘作为一项关键技术创新。这种方法提供的解决方案显著地 与显微核磁共振相比，提高了目前的最先进水平。我们相信，成功完成 提出的目标将显著提高我们对椎间盘生物学和椎间盘的认识。 成像。

Project Abstract Degeneration of the intervertebral disc (IVD) is a leading contributor towards back pain, an epidemic that costs billions of dollars in the US. The IVD consists of a proteoglycan(PG)-rich nucleus pulposus (NP) surrounded by a collagenous annulus fibrosus (AF) that together provide support and transmit complex loads. The IVD degenerative cascade involves a multifactorial progression of biological, biochemical, and structural changes that lead to the collapse of the disc structure and to compromised mechanical function. Despite its significant public health impact, the pathophysiology of disc degeneration remains unclear. The accumulation of Advanced Glycation End-products (AGEs) is associated with aging and diabetes. Increased AGEs has also been associated with IVD degeneration. AGEs form through nonenzymatic glycation, where extracellular sugars undergo Maillard rearrangement with amino acids to become protein adducts and crosslinks. AGES are known to impair the mechanical function of matrix proteins. Beyond matrix modifications, AGEs activate the cellular Receptor for Advanced Glycation Endproducts (RAGE), and RAGE signaling perpetuates immune and inflammatory responses. Because the IVD is avascular and has relatively low tissue remodeling, IVD tissues are susceptible to accumulate AGEs. Despite these observations, it is not known whether AGEs or RAGE signaling have a causal role in IVD degeneration. In this R01 application, we will determine the AGEs- and RAGE-mediated events as disease mechanisms for IVD degeneration. Specifically, we will identify the role of AGEs in altering IVD structure and function and define the necessity of RAGE-signaling in AGEs-mediated degeneration. If our hypotheses are supported, this will provide the putative targets to alleviate the degenerative cascade. The combination of in vivo and ex vivo- in vitro approaches will enable us to carefully dissect the systemic effects of high AGE-loads from tissue- specific effects of AGEs. We also will further develop the in vivo contrast-enhanced microCT of the intervertebral disc as a key technological innovation. This approach provides a resolution that significantly advances the current state-of-the-art compared to microMRIs. We believe that the successful completion of the proposed aims will significantly advance our knowledge of intervertebral disc biology and intervertebral disc imaging.