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）：我们建议通过靶向受体晚期糖化终产物（RAGE）来开发一种成像糖尿病的动脉粥样硬化的方法。由葡萄糖与蛋白质的非酶联连接形成的晚期糖基化最终产物（年龄）诱导细胞上的愤怒表达。 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型结构域组成，然后是两个C型域。年龄结合对愤怒的结合会诱导与斑块进程有关的多种信号通路。用动脉粥样硬化鉴定的其他炎症配体与愤怒结合，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旨在在小鼠，猪和人类中表现出免疫反应性的愤怒域的新型抗体。使用杂交瘤技术鼠单克隆抗体被生产，碎片和标记为99MTC，并在糖尿病APOE-/ - 小鼠的主动脉病变中显示摄取。在拟议的工作中，我们计划探索新型的愤怒，指示定量SPECT成像，以检测与非糖尿病性动脉粥样硬化和具有转基因愤怒表达的APOE - / - 小鼠相比，糖尿病表达的愤怒表达差异。我们建议探索愤怒成像，以检测愤怒表达的治疗性还原。最后，我们建议研究糖尿病性动脉粥样硬化猪中的愤怒作为转化步骤。这些实验的结果应建立愤怒的成像作为糖尿病管理的潜在有用工具。公共卫生相关性：糖尿病在美国流行。动脉粥样硬化正在进行糖尿病患者的加速过程。我们建议开发一种非侵入性成像技术，以鉴定糖尿病患者的加速动脉粥样硬化，以帮助疾病管理。