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

项目摘要 椎间盘退变（IVD）是导致背痛的主要原因，背痛是一种流行病， 在美国数十亿美元。IVD由富含蛋白多糖（PG）的髓核（NP）组成， 由胶原纤维环（AF）共同提供支撑并传递复杂载荷。的IVD 退行性级联反应涉及生物学、生物化学和结构变化的多因素进展 这导致椎间盘结构的塌陷和机械功能的损害。尽管其重要性 尽管对公众健康的影响很大，但椎间盘退变的病理生理学仍不清楚。 晚期糖基化终产物（AGEs）的积累与衰老有关， 糖尿病AGEs增加也与IVD变性有关。AGEs通过 非酶糖化，其中细胞外糖与氨基酸进行Maillard重排， 变成蛋白质加合物和交联物。已知AGES损害基质蛋白的机械功能。 除了基质修饰，AGEs激活细胞晚期糖基化终产物受体 （p53），并且p53信号传导使免疫和炎症反应持续存在。因为IVD是无血管的 并且具有相对低的组织重塑，IVD组织易于积累AGEs。尽管有这些 根据这些观察，尚不清楚AGEs或β-内酰胺酶信号传导是否在IVD变性中具有因果作用。 在R 01申请中，我们将确定AGEs和RAGE介导的事件作为疾病机制 用于IVD变性。具体而言，我们将确定AGEs在改变IVD结构和功能中的作用， 定义RAGE信号在AGEs介导的变性中的必要性。如果我们的假设得到支持， 将提供缓解退化级联的假定目标。体内和体外的结合- 体外方法将使我们能够仔细地剖析来自组织的高AGE负荷的全身效应， AGEs的具体影响。我们还将进一步开发活体对比增强microCT 椎间盘作为一项关键技术创新。这种方法提供了一种解决方案， 与microMRI相比，它提高了当前的技术水平。我们相信， 所提出的目标将大大提高我们对椎间盘生物学和椎间盘的认识。 显像

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.