RAGE-directed imaging in diabetes-induced accelerated atherosclerosis

RAGE 定向成像治疗糖尿病引起的加速动脉粥样硬化

基本信息

批准号：
7743062
负责人：
LYNNE L. JOHNSON
金额：
$ 40.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7743062
关键词：
Address Adult Advanced Glycosylation End Products Animal Model Antibodies Apolipoprotein E Apoptosis Arterial Fatty Streak Atherosclerosis Attenuated Binding C57BL/6 Mouse Cells Dependence Diabetes Mellitus Disease Disease Management Disease regression Dose Early treatment Epidemic Family suidae Genetic Glucose HMGB1 gene Human Hybridomas Image Imaging Techniques Immunoglobulins Inflammatory Knockout Mice LDL-Receptor Related Protein 1 Label Lesion Ligands Modeling Monitor Monoclonal Antibodies Mus Proteins Role S100A12 gene Serum Signal Pathway Signal Transduction Site Technology Testing Therapeutic Thromboplastin Time Tissues Tracer Work atherogenesis cell type design diabetes management diabetic extracellular glycemic control immunoreactivity in vivo inflammatory marker male member mouse model non-diabetic novel novel strategies prevent public health relevance receptor receptor expression research study single photon emission computed tomography tool uptake vascular inflammation

项目摘要

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.

描述（由申请人提供）：我们建议开发一种通过靶向受体高级糖化终产物（RAGE）对糖尿病中加速动脉粥样硬化进行成像的方法。葡萄糖与蛋白质非酶连接形成的高级糖基化终产物 (AGE) 诱导细胞上 RAGE 的表达。 RAGE 是免疫球蛋白超家族的一员，由一个胞外区和一个 V 型结构域及其后面的两个 C 型结构域组成。 AGE 与 RAGE 的结合会诱导参与斑块进展的多种信号通路。与动脉粥样硬化形成相关的其他炎症配体与 RAGE 结合，表明其在非糖尿病动脉粥样硬化中的作用。我们与合作者一起开发了一种针对 RAGE 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。使用杂交瘤技术生产、片段化并用 99mTc 标记的鼠单克隆抗体，并在糖尿病 apoE -/- 小鼠的主动脉病变中显示出摄取。在拟议的工作中，我们计划探索新型 RAGE 定向定量 SPECT 成像，以检测糖尿病与非糖尿病动脉粥样硬化以及具有基因修饰 RAGE 表达的 apoE -/- 小鼠中 RAGE 表达的差异。我们建议探索 RAGE 成像来检测 RAGE 表达的治疗性减少。最后，我们建议研究糖尿病动脉粥样硬化猪的 RAGE 定向成像作为转化步骤。这些实验的结果应该将 RAGE 定向成像确立为治疗糖尿病的潜在有用工具。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速。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。