Direct Detection and Characterization of Thrombosis In Vivo

体内血栓形成的直接检测和表征

• 批准号: 9980489
• 负责人: BRUCE ALAN SULLENGER
• 金额: $ 73.45万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980489
• 关键词: Acute; Address; Affinity; Animal Model; Antidotes; Azides; Binding; Biodistribution; Biological Models; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Cardiovascular system; Catheters; Chemistry; Cherry - dietary; Chronic; Coagulation Process; Complement; Complex; Deep Vein Thrombosis; Detection; Development; Disease; Event; Factor IXa; Fibrinolytic Agents; Fluorine; Future; Human; Image; Imaging Device; Individual; Investigation; Ischemic Stroke; Macaca mulatta; Modeling; Molecular Profiling; Mus; Myocardial Infarction; Nature; Nucleic Acid Biochemistry; Open Bite; Patients; Peripheral; Positron-Emission Tomography; Primates; Proteins; Prothrombin; Protocols documentation; Publishing; Pulmonary Embolism; RNA; Radiochemistry; Radiolabeled; Risk; Risk stratification; Scanning; Specificity; Stenosis; Surgical complication; Technology; Therapeutic; Therapeutic Intervention; Thrombin; Thrombosis; Thrombus; Time; Translating; Venous; Venous Thrombosis; age group; aged; antithrombin III-protease complex; aptamer; base; combinatorial chemistry; design; experience; imaging approach; imaging modality; imaging probe; in vivo; in vivo imaging; innovation; insight; molecular imaging; molecular modeling; mouse model; multidisciplinary; neurovascular; nonhuman primate; novel diagnostics; novel strategies; personalized care; personalized medicine; rapid detection; tool; translation to humans; von Willebrand Factor

PROJECT SUMMARY / ABSTRACT Vascular thrombosis is a major underlying factor in many cardiovascular, neurovascular, and related disorders, and is a significant post-surgical complication. Current imaging modalities used to assess thrombotic events present challenges because they primarily visualize the lack of blood flow rather than detailed information about a thrombus directly, and they cannot distinguish between newly formed and aged blood clots. Our team has previously demonstrated that high affinity and high specificity RNA aptamers can be generated against a number of coagulation proteins including thrombin and factor IXa. In addition, our team has demonstrated that aptamer-antidote pairs can be used as rapid binding-rapid reversal probes for real time detection of thrombi. The studies proposed in this application integrate aptamer-antidote pairs with sensitive total-body positron emission tomography (PET) imaging to develop a new approach in the way patients with thrombotic events can be stratified and subsequently treated. This proposal represents the convergence of multidisciplinary domains of expertise to explore a new team direction that will have a major impact on the field through the following Specific Aims: (1) Develop and evaluate aptamer-antidote pairs to perform rapid imaging of thrombi in mouse models for molecular thrombus profiling in vivo, and (2) Assess efficiency of radiolabeled aptamers for total-body PET in nonhuman primates. Preliminary results have demonstrated that aptamers can rapidly bind thrombin on active thrombi in vivo and that the antidotes can reverse such binding in under 5 minutes. In Specific Aim 1, we will further develop this technology by conducting studies in mice with aptamer-antidote pairs generated to thrombin, von Willebrand Factor, and platelet protein GPIIb/IIIa individually and combined. Findings will be adapted in Specific Aim 2 to the translational rhesus monkey model system using total-body PET that has demonstrated outstanding sensitivity. These investigations propose a new strategy to address characterization of thrombi in vivo and include a multidisciplinary translational team with expertise in nucleic acid biochemistry, combinatorial chemistry, antithrombotic agents, novel diagnostic imaging tools and methods, and a nonhuman primate model system of profound translational importance.

项目概要/摘要 血管血栓形成是许多心血管、神经血管和相关疾病的主要潜在因素， 并且是一种重要的术后并发症。当前用于评估血栓事件的成像方式 存在挑战，因为他们主要可视化血流缺乏而不是详细信息 他们无法直接识别血栓，无法区分新形成的血块和老化的血块。我们的团队 先前已经证明，可以针对特定的RNA生成高亲和力和高特异性的RNA适体。 凝血蛋白的数量，包括凝血酶和因子 IXa。此外，我们的团队已经证明 适体-解毒剂对可用作快速结合-快速逆转探针，用于实时检测血栓。 本申请提出的研究将适体-解毒剂对与敏感的全身正电子结合起来 发射断层扫描 (PET) 成像开发治疗血栓事件患者的新方法 可以分层并随后进行治疗。该提案代表了多学科的融合 专业领域探索新的团队方向，这将通过以下方式对该领域产生重大影响 具体目标如下： (1) 开发并评估适体-解毒剂对，以对血栓进行快速成像 用于体内分子血栓分析的小鼠模型，以及（2）评估放射性标记适体的效率 非人类灵长类动物的全身 PET。初步结果表明适配体可以快速结合 体内的活性血栓上有凝血酶，解毒剂可以在 5 分钟内逆转这种结合。在 具体目标1，我们将通过在小鼠身上进行适体解毒剂研究来进一步开发这项技术 分别和组合生成凝血酶、血管性血友病因子和血小板蛋白 GPIIb/IIIa 对。 具体目标 2 中的研究结果将适用于使用全身的转化恒河猴模型系统 PET 表现出出色的灵敏度。这些调查提出了一项新策略来解决 体内血栓的表征，包括具有核酸专业知识的多学科翻译团队 酸性生物化学、组合化学、抗血栓剂、新型诊断成像工具和 方法，以及具有深远翻译重要性的非人类灵长类动物模型系统。