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晚期糖化终产物受体（RAGE）来成像糖尿病加速动脉粥样硬化的方法。晚期糖基化终产物（AGEs）由葡萄糖与蛋白质的非酶连锁形成，可诱导RAGE在细胞上的表达。RAGE是免疫球蛋白超家族的成员，由一个细胞外区域和一个v型结构域以及两个c型结构域组成。AGEs与RAGE结合可诱导参与斑块进展的多种信号通路。其他与动脉粥样硬化有关的炎症配体与RAGE结合，暗示其在非糖尿病性动脉粥样硬化中的作用。我们与我们的合作者开发了一种针对RAGE的v结构域的新型抗体，旨在在小鼠，猪和人类中显示免疫反应性。采用杂杂瘤技术制备小鼠单克隆抗体，片段化并标记99mTc，并在糖尿病apoE -/-小鼠主动脉病变中显示摄取。在拟议的工作中，我们计划探索新的RAGE定向定量SPECT成像，以检测糖尿病与非糖尿病性动脉粥样硬化中RAGE表达的差异，以及基因修饰RAGE表达的apoE -/-小鼠。我们建议探索RAGE成像来检测RAGE表达的治疗性降低。最后，我们建议研究RAGE在糖尿病动脉粥样硬化猪中的定向成像作为一个转化步骤。这些实验的结果应该确立RAGE定向成像作为糖尿病管理的潜在有用工具。公共卫生相关性：糖尿病在美国已成为流行病。糖尿病患者的动脉粥样硬化进程加快。我们建议发展一种非侵入性成像技术来识别糖尿病患者加速动脉粥样硬化，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.