Soluble Receptor for Advanced Glycation End Products for Therapeutic Application

细胞信号通过晚期糖基化终产物受体（RAGE）导致促炎反应。rage介导的炎症与炎症性疾病有关，包括糖尿病、动脉粥样硬化和阿尔茨海默病。RAGE的剪接或蛋白裂解形式被称为可溶性RAGE (sRAGE)，其功能是作为天然诱饵对抗RAGE信号传导。在动物模型中已经证明，使用sRAGE可以阻断动脉粥样硬化，并稳定血管壁上现有的斑块。此外，sRAGE还能防止血管损伤引起的新生内膜的形成，从而抑制再狭窄。

Cellular signaling via receptor for advanced glycation end products (RAGE) results in pro-inflammatory responses. RAGE-mediated inflammation has been implicated in inflammatory diseases including diabetes, atherosclerosis, and Alzheimers disease. The spliced or proteolytically cleaved form of RAGE is referred as soluble RAGE (sRAGE), which functions as a natural decoy counter-effecting RAGE signaling. It has been demonstrated in animal models that administration of sRAGE blocks atherogenesis, and stabilizes existing plaques on the vessel wall. In addition, sRAGE also prevents the formation of neointima prompted by vascular injuries and hence inhibits restenosis. We have developed Chinese Hamster Ovary (CHO) cell lines that stably express sRAGE, and the accompanied affinity purification strategies that produce homogenous sRAGE. Systemic studies of sRAGE application in restenosis animal models have been completed, and data have been analyzed. Our results showed that sRAGE produced in our laboratory exhibits 1000 x higher potency than that of previously reported. In addition to blocking restenosis, we also tested sRAGE blockage on infarct animal models and obtained promising preliminary results. We also performed studies to explore the molecular basis of the observed high potency of sRAGE and found that N-glycan structure in sRAGE contributes to its bioactivity. We are currently collaborating with Johns Hopkins University to determine the N-glycan profile and structure, aiming at further potentiating sRAGE bioactivity. To further develop sRAGE as an effective therapeutic product, we, in collaboration with Department of Energy's Ames Laboratory, also initiated studies using mesoporous silica nanoparticle-based drug delivery system for a more effective in vivo delivery, and controlled release. We hope to develop nanoparticle delivery-release system carrying sRAGE in combination with other anti-inflammatory and anti-thrombosis drug to effectively combat vascular diseases. The reagent is currently under development, and is not available for public or commercial usage. To overcome technical hurdles for expression and detection of sRAGE, we also developed a set of expression modules that facilitate subcloning, cell-surface expression. and epitope tagging of mammalian membrane proteins. U.S. Provisional Patent (No. 61/142,531) has been awarded to this invention, and NIH is currently advertising the invention. R&D Status: Pre-clinical in vitro.