Strategies and functional outcomes of enhancing in vivo production of soluble rage isoforms

项目摘要/摘要 通过与晚期糖基化终末产物受体(AGEs)的结合而激活RAGE 配体，通过持续性和周期性调节糖尿病并发症的发生和发展 核因子-ΚB的激活直接靶向RAGE作为一种治疗策略在很大程度上 不成功。然而，在体内，RAGE信号可以被ADAM10(一种去整合素和 金属蛋白酶10)引导RAGE胞外结构域的蛋白水解性切割，从而产生一种可溶的 从细胞中释放出来并进入循环的RAGE(SRAGE)的异构体。保持高水平 循环sRAGE的水平是有利的，因为sRAGE将隔离RAGE配体并防止RAGE细胞 发信号。我们的长期目标是确定预防和治疗糖尿病并发症的策略。 通过有氧运动，我们阐明了ADAM10上调增加RAGE的机制 正在脱落。有氧运动为肌肉脱脂机制研究提供了一种独特的模型 收缩为组织重塑和代谢环境的分解提供了刺激， 发炎。我们的中心假设是骨骼肌在数量上是SRAGE的重要来源 循环中出现和维持健康水平的总SRAGE促进心脏代谢 健康。其基本原理是，一旦ADAM10激活和SRAGE生成的机制 阐明，在预防和治疗糖尿病并发症方面取得进展是可能的。 在值得注意的初步数据的推动下，我们提出了三个具体目标来追求我们的核心假设： (1)我们将测试急性和慢性运动对产生SRAGE亚型的影响(2)我们将确定 阿维A治疗对RAGE介导的炎症的影响和(3)我们将探索新的保护作用 在微血管系统中。这项工作具有创新性，因为对狂暴外域脱落的研究 人类骨骼肌挑战了目前对年龄/愤怒生物学的理解以及已知的 ADAM10活性。在这些研究完成后，我们期望我们将确定一部小说 ADAM10的激活机制和SARAGE产生的重要组织来源。最终，这样的一个 洞察力有可能改善糖尿病及其相关疾病的预防和治疗管理 并发症，从而减轻了影响全球约3.47亿人的经济和社会负担 糖尿病。

Project Summary /Abstract Activation of RAGE (receptor of advanced glycation endproducts (AGEs)), via binding of AGEs and other ligands, modulates the development and progression of diabetic complications through persistent and cyclic activation of nuclear factor-ΚB. Targeting RAGE directly as a therapeutic strategy has largely been unsuccessful. However, RAGE signaling can be interrupted, in vivo, by ADAM10 (a disintegrin and metalloproteinase 10) directed proteolytic cleavage of the RAGE ectodomain, and thus creating a soluble isoform of RAGE (sRAGE) that is released from the cell and appears into the circulation. Maintaining high levels of circulating sRAGE is advantageous as sRAGE will sequester RAGE ligands and prevent RAGE cell signaling. Our long-term goal is to identify strategies for the prevention and treatment of diabetic complications. Using aerobic exercise, we have elucidated a mechanism for ADAM10 upregulation to increase RAGE shedding. Aerobic exercise presents a unique model for mechanistic study of RAGE shedding as muscle contraction provides stimuli for tissue remodeling and resolution of the metabolic milieu that drives inflammation. Our central hypothesis is that skeletal muscle is a quantitatively important source of sRAGE appearance in the circulation and maintenance of healthy levels of total sRAGE promotes cardiometabolic health. The rationale is that once the mechanisms of ADAM10 activation and sRAGE generation are elucidated, progress towards the prevention and treatment of diabetic complications may be possible. Compelled by noteworthy preliminary data, we propose three specific aims to pursue our central hypothesis: (1) we will test the effects of acute and chronic exercise in generating sRAGE isoforms (2) we will determine the effects of acitretin therapy on RAGE mediated inflammation and (3) we will explore new protective effects of sRAGE in the microvasculature. The work is innovative because the study of RAGE ectodomain shedding in human skeletal muscle challenges the current understanding of AGE/RAGE biology and the known behavior of ADAM10 activity. At the completion of these studies, it is our expectation that we will have identified a novel mechanism of ADAM10 activation and an important tissue source of sRAGE production. Ultimately, such an insight has the potential to improve the prevention and therapeutic management of diabetes and its complications, thus reducing the financial and social burden that affects the ~347 million people worldwide with diabetes.