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

• 批准号: 7996594
• 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
• 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/7996594
• 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; Health; Human; Hybridomas; Image; Imaging Techniques; Immunoglobulins; Inflammatory; Knockout Mice; LDL-Receptor Related Protein 1; Label; Lesion; Ligands; Matrix Metalloproteinases; 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; receptor; receptor expression; research study; single photon emission computed tomography; tool; uptake; vascular inflammation

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）：我们建议开发一种方法，通过靶向受体晚期糖化终产物（AGEs）来成像糖尿病中加速的动脉粥样硬化。糖基化终末产物（Advanced Glycation End Products，AGEs）是葡萄糖与蛋白质非酶结合形成的糖基化终末产物，可诱导胰岛细胞表达糖基化终末产物。CD 45是免疫球蛋白超家族的成员，由细胞外区和一个V型结构域以及随后的两个C型结构域组成。AGEs结合到斑块中可诱导多种参与斑块进展的信号通路。其他与动脉粥样硬化形成有关的炎性配体结合到糖尿病相关的动脉粥样硬化中，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，我们已经开发了一种新的抗体的V-域的设计显示免疫反应性在小鼠，猪和人。使用杂交瘤技术产生鼠单克隆抗体，将其片段化并用99 mTc标记，并显示在糖尿病apoE -/-小鼠的主动脉病变中的摄取。在拟议的工作中，我们计划探索新的α-淀粉样蛋白定向定量SPECT成像，以检测糖尿病动脉粥样硬化与非糖尿病动脉粥样硬化和apoE -/-小鼠与基因修饰的α-淀粉样蛋白表达的差异。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中研究磁共振成像作为一个平移步骤。这些实验的结果应该建立作为一个潜在的有用的工具，在糖尿病的管理，糖尿病的直接成像。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。我们建议开发一种非侵入性成像技术，以确定糖尿病患者的加速动脉粥样硬化，以帮助疾病管理。