Molecular Imaging Probes for Reporting on Vascular Oxidative Response

用于报告血管氧化反应的分子成像探针

• 批准号: 8423753
• 负责人: Alexei A Bogdanov
• 金额: $ 30.63万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423753
• 关键词: Aneurysm; Area; Arterial Fatty Streak; Binding; Biological Models; Blood Vessels; Brain; Cardiovascular Diseases; Cell Surface Proteins; Cell surface; Cells; Cessation of life; Developed Countries; Developing Countries; Diagnosis; Disease; Disease Progression; Early treatment; Endothelial Cells; Enzymes; Exocytosis; Experimental Models; Extracellular Matrix; Heart; Hydrogen Peroxide; Image; Imagery; In Vitro; Inflammation; Lesion; Life; Mediator of activation protein; Methods; Modeling; Molecular Probes; Monitor; Myocardial Infarction; NADPH Oxidase; Nuclear; Oryctolagus cuniculus; Pathology; Pathway interactions; Patients; Peroxidases; Population; Production; Property; Radioisotopes; Reporter; Reporting; Research; Rupture; Signal Transduction; Site; Stroke; Superoxide Dismutase; Superoxides; Testing; Tissues; Toxic effect; Toxicity Tests; Translations; Vascular blood supply; base; cost; design; imaging probe; in vitro testing; in vivo; inflammatory marker; molecular imaging; monocyte; mortality; novel; prevent; public health relevance; response; sensor; statistics; tumor; vascular inflammation

DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of mortality in developed countries claiming 870,000 deaths/year in US alone (year 2004 statistics). With cases on the rise in the developing countries as well the associated raising costs in managing the afflicted population will have global implications and urgently require paradigm-shifting approaches to diagnosis and monitoring of disease progression. In this proposal we suggest to develop and apply novel molecular imaging probes for detecting the changes in the repertoire of cell-generated mediators typical of local inflammation in the vascular wall as the early signal of cardiovascular disease progression. Myeloperoxidase (MPO, one of the components released by PMNs via triggered exocytosis) is a unique catalytically active marker of inflammation sites, implicated in progression of vascular pathologies, e.g. unstable atheroma. We previously developed and applied MR signal amplification strategy for imaging of MPO enzymatic activity using paramagnetic bisamides of GdDTPA as reducing substrates of MPO. Due to the fact that MPO binds to the cell surface and is retained at the site of inflammation, the potential applications of MPO imaging are numerous and range from stroke imaging to imaging of vascular wall pathologies. Building on our previous research applying MR and nuclear imaging to visualization of culprits of inflammation of the vascular wall we propose to perform optimization of MPO molecular imaging probe with the focus on probe stability and potential translation of our research. We also propose to design novel dual-function sensors for MPO imaging. MPO activity in vascular lesions is rate-limited by the rates of local hydrogen peroxide production. Hydrogen peroxide is a product of superoxide/hydrogen peroxide pathway activation in many cells populating blood vessel wall (PMN, monocytes and endothelial cells), which respond by activating intracellular NADPH oxidase. We propose to synthesize and test in model systems paramagnetic superoxide dismutase (SOD) mimic-MPO substrates based on chelated paramagnetic Mn(II) and Gd(III), which supply additional hydrogen peroxide, and simultaneously report on MPO activity due to the ability to bind to proteins of cell surface and extracellular matrix. We propose optimization steps, feasibility testing using radioisotope methods and toxicity testing before in vivo imaging. The proposal will pursue three major aims: 1) develop novel synthetic approaches and building blocks for optimizing myeloperoxidase reporter probes (MPO-specific paramagnetic chelates); 2) characterize the developed molecular imaging probes: enzyme reporting, dismutase mimic properties and stability in vitro; 3) perform testing of molecular probes for imaging oxidative response in vivo.

描述（由申请人提供）： 心血管疾病是发达国家死亡率的主要原因，仅美国（2004年统计）每年死亡870,000人。随着发展中国家的案件在增加，以及在管理受伤人群的管理方面的提高成本将具有全球影响，并且迫切需要转移范式的诊断和监测疾病进展的方法。在此提案中，我们建议开发和应用新颖的分子成像探针来检测血管壁中典型局部炎症的曲目的变化，作为心血管疾病进展的早期信号。脊髓过氧化物酶（MPO，PMN通过触发的胞吐释放的成分之一）是炎症部位的独特催化活性标记，涉及血管病理的进展，例如。不稳定的动脉瘤。我们以前使用GDDTPA的顺磁双酰胺作为减少MPO的底物进行了MPO酶活性的成像，以制定并应用了MR信号扩增策略。由于MPO与细胞表面结合并保留在炎症部位，因此MPO成像的潜在应用是众多的，从中风成像到血管壁病理的成像。在我们先前的研究基础上，将MR和核成像应用于血管壁炎症的可视化，我们建议对MPO分子成像探针进行优化，重点是探测稳定性和研究的潜在翻译。我们还建议为MPO成像设计新型的双功能传感器。血管病变中的MPO活性是由局部过氧化氢生产速率限制的。过氧化氢是许多填充血管壁（PMN，单核细胞和内皮细胞）的细胞中超氧化物/过氧化氢途径激活的产物，这些细胞通过激活细胞内NADPH氧化酶做出反应。我们建议基于螯合的丙二酰磁管MN（II）和GD（III），在模型系统中合成和测试模型超氧化物歧化酶（SOD）模拟MPO底物，该型过氧化氢，并同时报告了由于能够与细胞表面和外部外部extracellalular Matrix蛋白结合的能力而同时报告MPO活性。我们提出优化步骤，使用放射性同位素方法进行可行性测试以及体内成像之前的毒性测试。该提案将追求三个主要目的：1）开发新型的合成方法和构建基础，以优化髓过氧化物酶报告基因探针（MPO特异性顺磁性螯合物）； 2）表征开发的分子成像探针：酶报告，歧义酶模仿特性和体外稳定性； 3）对分子探针进行测试，以在体内成像氧化反应。