The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease.
The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease.
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DOI：
10.1517/14728222.2016.1111873
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发表时间：
2016
影响因子：
5.8
通讯作者：
Schmidt AM
中科院分区：
文献类型：
--
作者：
Ramasamy R;Shekhtman A;Schmidt AM
本文综述了免疫球蛋白超家族的多配体受体，即晚期糖基化终产物受体(RAGE)。RAGE的多个配体在细胞应激环境中的积累与慢性病和自然衰老的病理生物学有关。在这篇综述中，我们对RAGE的配体以及这些配体家族在疾病中的意义进行了讨论。我们回顾了关于配体-RAGE相互作用在自然衰老后果中的作用；糖尿病的大血管和微血管并发症；肥胖和胰岛素抵抗；自身免疫性疾病和慢性炎症；肿瘤和阿尔茨海默病的最新文献。我们讨论了RAGE通过其细胞内结合效应分子FORMIN DIAPH1传递信号的机制。还综述了RAGE细胞质结构域与DIAPH1的FH1(福尔明同源1)结构域结合的物理化学证据及其后果。我们讨论了目前在临床前和临床研究中RAGE拮抗的方式。最后，我们提出了潜在地靶向RAGE细胞质结构域-DIAPH1相互作用的基本原理，作为一种在RAGE配体聚集和信号的慢性疾病和衰老的病理环境中进行治疗干预的逻辑策略。
This review focuses on the multi-ligand receptor of the immunoglobulin superfamily, receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging. In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand-RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; tumors and Alzheimer’s disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule, the formin DIAPH1. Physico-chemical evidence by which the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences, is also reviewed. We discuss the modalities of RAGE antagonism currently in pre-clinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain-DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging in which RAGE ligands accumulate and signal.