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: 7761172
• 负责人: Alexei A Bogdanov
• 金额: $ 33.69万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761172
• 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; Figs - dietary; 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. PUBLIC HEALTH RELEVANCE: Diseased blood vessel walls frequently develop lesions that can become unstable and rupture. The rupture leads to blocking blood supply and death of tissues in the brain and heart and may result in debilitating disease and loss of life. We propose to develop agents that can report on areas of instability in blood vessels and detoxify some of the reactive molecules that cause instability, which has implications in preventing heart attacks and strokes by identifying patients who carry unstable lesions and who can benefit from early treatment of such unstable lesions.

描述（由申请人提供）： 心血管疾病是发达国家死亡的主要原因，仅美国每年就有 870,000 人死亡（2004 年统计）。随着发展中国家病例的增加以及管理受影响人口的相关成本的增加，将产生全球影响，并迫切需要改变范式的方法来诊断和监测疾病进展。在本提案中，我们建议开发和应用新型分子成像探针，用于检测血管壁局部炎症典型的细胞生成介质的变化，作为心血管疾病进展的早期信号。髓过氧化物酶（MPO，中性粒细胞通过触发胞吐作用释放的成分之一）是炎症部位的独特催化活性标记物，与血管病理学的进展有关，例如血管病变。不稳定的动脉粥样硬化。我们之前开发并应用了 MR 信号放大策略，使用 GdDTPA 的顺磁性双酰胺作为 MPO 的还原底物来成像 MPO 酶活性。由于 MPO 与细胞表面结合并保留在炎症部位，因此 MPO 成像的潜在应用有很多，范围从中风成像到血管壁病理成像。基于我们之前应用 MR 和核成像可视化血管壁炎症罪魁祸首的研究，我们建议对 MPO 分子成像探针进行优化，重点关注探针稳定性和我们研究的潜在转化。我们还建议设计用于 MPO 成像的新型双功能传感器。血管病变中的 MPO 活性受到局部过氧化氢生成速率的限制。过氧化氢是血管壁上许多细胞（PMN、单核细胞和内皮细胞）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。我们建议在模型系统中合成和测试基于螯合顺磁性 Mn(II) 和 Gd(III) 的顺磁性超氧化物歧化酶 (SOD) 模拟 MPO 底物，它们提供额外的过氧化氢，并同时报告 MPO 活性，因为能够与细胞表面和细胞外基质的蛋白质结合。我们提出了优化步骤、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标：1）开发新的合成方法和构建模块来优化髓过氧化物酶报告探针（MPO 特异性顺磁螯合物）； 2) 表征所开发的分子成像探针：酶报告、歧化酶模拟特性和体外稳定性； 3) 对体内氧化反应成像的分子探针进行测试。 公共卫生相关性： 患病的血管壁经常会出现病变，导致不稳定和破裂。破裂会导致大脑和心脏的血液供应受阻和组织死亡，并可能导致衰弱疾病和死亡。我们建议开发能够报告血管不稳定区域并解毒一些导致不稳定的反应分子的药物，这对于通过识别携带不稳定病变的患者以及谁可以从早期治疗中受益来预防心脏病发作和中风具有重要意义。这种不稳定的病变。