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: 8197198
• 负责人: LYNNE L. JOHNSON
• 金额: $ 39.85万
• 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/8197198
• 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; 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

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.

我们建议开发一种方法，通过靶向受体成像糖尿病加速动脉粥样硬化 高级糖化终产物（Advanced Glycated Endproducts，简写为AGEs）。晚期糖基化终产物（AGEs）是由糖基化终产物形成的。 葡萄糖与蛋白质的非酶促连接诱导了细胞的表达。是一个成员， 免疫球蛋白超家族，由一个胞外区和一个V型结构域，随后是两个 C型结构域。AGEs与β-内酰胺酶结合诱导多种信号通路参与斑块形成 进展其他与动脉粥样硬化形成有关的炎症配体与血管紧张素Ⅱ结合，暗示其在非动脉粥样硬化中的作用。 糖尿病性动脉粥样硬化与我们的合作者，我们已经开发了一种新的抗体的V-结构域的 设计用于在小鼠、猪和人中显示免疫反应性的抗体。利用杂交瘤技术 制备单克隆抗体，将其片段化，并用99 mTc标记，并显示在主动脉病变中摄取 糖尿病apoE -/-小鼠。在所提出的工作中，我们计划探索新的荧光定向定量SPECT 成像以检测糖尿病性动脉粥样硬化与非糖尿病性动脉粥样硬化相比， apoE -/-小鼠与基因修饰的apoE表达。我们建议探索磁共振成像， 治疗性降低β-内酰胺酶表达。最后，我们建议调查的直接成像， 糖尿病动脉粥样硬化猪作为一个翻译步骤。这些实验的结果应该建立一个 定向成像作为糖尿病管理中潜在有用的工具。

项目成果

Beneficial Effect of Glucose Control on Atherosclerosis Progression in Diabetic ApoE(-/-) Mice: Shown by Rage Directed Imaging.

血糖控制对糖尿病 ApoE(-/-) 小鼠动脉粥样硬化进展的有益影响：通过愤怒定向成像显示。

• DOI: 10.1155/2014/695391
• 发表时间: 2014
• 期刊: International journal of molecular imaging
• 作者: Tekabe,Yared;Kollaros,Maria;Li,Qing;Zhang,Geping;Li,Chong;Schmidt,AnnMarie;Johnson,LynneL
• 通讯作者: Johnson,LynneL