Soluble Receptor for Advanced Glycation End Products for Therapeutic Application

用于治疗应用的高级糖基化终产物的可溶性受体

• 批准号: 7964076
• 负责人: Edward Lakatta
• 金额: $ 8.81万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964076
• 关键词: Advanced Glycosylation End Products; Advertising; Affinity Chromatography; Alzheimer' s Disease; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Award; Basic Science; Biochemical; Blood Vessels; Cardiovascular Diseases; Cell Line; Cell surface; Chemistry; Chinese Hamster Ovary Cell; Cleaved cell; Clinic; Clinical Trials; Collaborations; Complementary DNA; Detection; Development; Diabetes Mellitus; Disease; Dose; Drug Delivery Systems; Epitopes; Future; Genetic Engineering; Goals; Half-Life; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Legal patent; Ligand Binding; Mediating; Membrane Proteins; Modeling; Molecular; Molecular Biology; Pharmaceutical Preparations; Physiology; Process; Property; RNA Splicing; Reagent; Reporting; Signal Transduction; Silicon Dioxide; Staging; System; Testing; Therapeutic; Thrombosis; United States National Institutes of Health; Vascular Diseases; Vascular Endothelial Cell; Work; atherogenesis; base; clinical application; combat; controlled release; experience; in vivo; monocyte; nanoparticle; neointima formation; particle; pre-clinical; prevent; receptor; research and development; restenosis

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, 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. Preliminary studies in animal restenosis models showed that sRAGE produced in our lab has significantly higher efficacy than reported. Current work has focused on determination of effective blocking dose of sRAGE in restenosis animal models. Assessment of molecular basis of such high efficacy is underway, and in vivo half-life and ligand binding capacity are also underway. To further develop sRAGE as an effective therapeutic product, we, in collaboration with Department of Energys 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.

通过受体的细胞信号传导晚期糖基化最终产物（RAGE）导致促炎反应。愤怒介导的炎症与包括糖尿病，动脉粥样硬化，阿尔茨海默氏病在内的炎症性疾病有关。愤怒的拼接或蛋白水解裂片形式称为可溶性愤怒（SRAGE），该愤怒（Srage）是自然诱饵反应的愤怒信号传导。在动物模型中已经证明了SRAGE的给药可阻止动脉粥样硬化，并稳定了容器壁上现有的斑块。此外，Srage还防止了血管损伤引起的新内膜的形成，因此抑制再狭窄。 我们已经开发了稳定表达SRAGE的中国仓鼠卵巢（CHO）细胞系，并产生同质性的亲和力纯化策略。动物再狭窄模型的初步研究表明，我们实验室产生的SRAGE的功效明显高于报道。当前的工作集中在确定再狭窄动物模型中的有效阻断SRAGE的有效阻断剂量。对这种高疗效的分子基础的评估正在进行中，并且还在进行体内半衰期和配体结合能力。 为了进一步发展为有效的治疗产品，我们与Energys Ames实验室合作，还使用基于中孔二氧化硅纳米粒子的药物输送系统启动了研究，以更有效的体内递送和受控释放。我们希望开发携带Srage的纳米颗粒递送释放系统，并结合其他抗炎和抗凝血界药物，以有效地打击血管疾病。 该试剂目前正在开发中，不适用于公共或商业用法。 为了克服用于表达和检测SRAGE的技术障碍，我们还开发了一组表达模块，可促进亚克隆，细胞表达。和哺乳动物膜蛋白的表位标记。美国临时专利（第61/142,531号）已授予本发明，NIH目前正在宣传本发明。研发状态：体外临床前。