RAGE-directed imaging in diabetes-induced accelerated atherosclerosis

描述(由申请人提供)：我们建议开发一种通过靶向受体晚期糖化终末产物(RAGE)来成像糖尿病加速动脉粥样硬化的方法。糖基化终末产物(AGEs)是葡萄糖与蛋白质非酶连接形成的产物，可诱导细胞上RAGE的表达。RAGE是免疫球蛋白超家族的成员，由一个胞外区和一个V型结构域以及两个C型结构域组成。AGEs与RAGE结合可诱导多种信号通路参与斑块的进展。其他与动脉粥样硬化相关的炎性配体与RAGE结合，暗示其在非糖尿病动脉粥样硬化中的作用。与我们的合作者一起，我们开发了一种针对RAGE的V区的新型抗体，旨在显示小鼠、猪和人类的免疫反应性。用杂交瘤技术制备小鼠单抗，用99mTc标记，显示糖尿病apoE-/-小鼠的主动脉病变摄取。在这项拟议的工作中，我们计划探索新的RAGE导向的定量SPECT成像，以检测糖尿病与非糖尿病动脉粥样硬化患者以及具有转基因RAGE表达的apoE-/-小鼠RAGE表达的差异。我们建议探索RAGE成像来检测RAGE表达的治疗减少。最后，我们建议在糖尿病动脉粥样硬化猪身上研究RAGE定向成像作为翻译步骤。这些实验的结果应该会建立RAGE定向成像作为一种潜在的有用工具来管理糖尿病。与公共健康相关：糖尿病已经在美国流行起来。动脉粥样硬化在糖尿病患者中会加速发展。我们建议开发一种非侵入性成像技术来识别糖尿病患者加速的动脉粥样硬化，以帮助疾病管理。

DESCRIPTION (provided by applicant): We propose to develop an approach to imaging accelerated atherosclerosis in diabetes by targeting Receptors Advanced Glycated Endproducts (RAGE). Advanced Glycation End Products (AGEs) formed by the nonenzymatic linkage of glucose to proteins induce the expression of RAGE on cells. RAGE is a member of the immunoglobulin superfamily, comprised of an extracellular region and one V-type domain followed by two C-type domains. Binding of AGEs to RAGE induces multiple signaling pathways involved in plaque progression. Other inflammatory ligands identified with atherogenesis bind to RAGE implicating its role in non- diabetic atherosclerosis. With our collaborators we have developed a novel antibody against the V-domain of RAGE designed to display immunoreactivity in mice, pigs and human. Using hybridoma technology murine monoclonal antibodies were produced, fragmented, and labeled with 99mTc, and show uptake in aortic lesions of diabetic apoE -/- mice. In the proposed work we plan to explore novel RAGE directed quantitative SPECT imaging to detect differences in RAGE expression in diabetic compared to non-diabetic atherosclerosis and in apoE -/- mice with genetically modified RAGE expression. We propose to explore RAGE imaging to detect therapeutic reduction in RAGE expression. Finally we propose to investigate RAGE directed imaging in diabetic atherosclerotic swine as a translational step. The results of these experiments should establish RAGE directed imaging as a potentially useful tool in the management of diabetes. PUBLIC HEALTH RELEVANCE: Diabetes has become epidemic in the US. Atherosclerosis takes an accelerated course in diabetics. We propose to develop a non-invasive imaging technique to identify accelerated atherosclerosis in diabetics to aid in disease management.