A theranostic approach for risk stratification and intervention of deep vein thrombosis.

深静脉血栓形成风险分层和干预的治疗诊断方法。

基本信息

批准号：
9767271
负责人：
Nicole Franziska Steinmetz
金额：
$ 55.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767271
关键词：
Accounting Affinity American Anatomy Antibodies Attenuated Bacteriophages Benchmarking Biodistribution Biopsy Blood Blood Platelets Blood Tests Cells Chemistry Chronic Contrast Media Contrast Sensitivity Data Deep Vein Thrombosis Detection Development Diagnosis Diagnostic Diagnostic Procedure Disease Disease Progression Drug Delivery Systems Drug Kinetics Engineering Fibrin fragment D Fibrinolytic Agents Health Care Costs Hemorrhage Hemostatic function Histology Hyperacusis Image Imaging Phantoms Imaging Techniques In Vitro Inflammation Institutes Intervention Intracranial Hemorrhages Knock-out Libraries Ligands Link Magnetic Resonance Imaging Methods Modality Molecular Molecular Profiling Molecular Target Monitor Mus Myelogenous Non-Invasive Cancer Detection Pathway interactions Patients Peptides Phlebography Plasminogen Activator Platelet Activation Platelet aggregation Proteins Protocols documentation Recurrence Resolution Risk Risk stratification Roentgen Rays S100A9 gene Safety Shapes Signal Transduction Specificity Stenosis Surface Survivors Testing Therapeutic Therapeutic Intervention Thromboembolism Thrombosis Thrombus Time Tissues Toxic effect Treatment Efficacy Ultrasonography Venous base cell type clinical Diagnosis combinatorial follow-up imaging approach imaging modality imaging study in vivo intima media macrophage monocyte mouse model neutrophil novel strategies outcome forecast success targeted agent targeted delivery targeted treatment theranostics

项目摘要

Summary Data suggest that 60,000-100,000 Americans die of venous thromboembolism (VTE) each year, that 50% of the surviving patients will have long-term complications, and that about one third of the survivors have recurrence within 10 years. The US healthcare costs are staggering and carry a high burden for treatment of VTE patients; it is estimated that $10 billion US dollars are spent each year accounting for treatment and man- agement of VTE. There is a critical need for both, accurate clinical diagnosis of VTE, in particular deep vein thrombosis (DVT), and targeted therapies to reduce safety issues, specifically intracranial hemorrhage, asso- ciated with thrombolytic drugs. Current diagnostic methods are not accurate: blood test assessing D-dimer blood levels are only indicative of DVT. Imaging techniques such as X-ray venography and ultrasonography reflect changes in the venous anatomy, but these modalities do not provide information about the molecular composition of the thrombus. Only biopsy followed by histology gives the molecular information needed for ac- curate prognosis, but these methods are invasive and associated with significant risks. We propose a non- invasive, magnetic resonance imaging (MRI) approach using a targeted contrast agent to gain information of the thrombus molecular composition to aid prognosis. The probe will also be engineered to aid therapeutic in- tervention through disruption of disease-promoting pathways or drug delivery. The integrated imaging and therapeutic capabilities will also facilitate longitudinal follow-up to monitor disease progression and therapy success. We will target myeloid-related protein 14 (MRP-14, also referred to as S100A9). MRP-14 is secreted from activated neutrophils, monocytes, and platelets and our data indicate a link between MRP-14 and DVT. MRP-14 is found at high levels in DVT and knockout of MRP-14 in mice attenuates DVT formation. Using a phage library combinatorial approach, we identified specific peptide ligands that target MRP-14 with high speci- ficity. We will integrate the MRP-14 binders with a macromolecular MRI contrast agent, and we will develop an MRI protocol for non-invasive detection of MRP-14 to aid diagnosis and prognosis of DVT. At the same time, we will develop a targeted therapeutic approach: first, we will test whether disruption of the MRP-14 function can attenuate DVT formation. Second, we will assess MRP-14 targeted delivery of the thrombolytic drug plas- minogen activator (tPA). The targeted therapeutic approach holds the potential to overcome bleeding risks as- sociated with the treatment. Disease progression and therapy success will be evaluated in a longitudinal MRI study.

概括数据显示，每年有 60,000-100,000 名美国人死于静脉血栓栓塞 (VTE)， 50%的幸存患者会出现长期并发症，大约三分之一的幸存者有 10年内复发。美国的医疗费用是惊人的，并且给治疗带来了沉重的负担。 VTE 患者每年估计花费 100 亿美元用于治疗和护理 VTE 的治疗迫切需要准确的 VTE 临床诊断，特别是深静脉诊断。血栓形成（DVT），以及减少安全问题的靶向治疗，特别是颅内出血，目前的诊断方法并不准确：血液检查评估 D-二聚体。血液水平仅指示 DVT 的影像学技术，例如 X 射线静脉造影和超声检查。反映静脉解剖结构的变化，但这些模式不提供有关分子的信息只有活检和组织学检查才能提供治疗所需的分子信息。治疗预后，但这些方法是侵入性的，并且与重大风险相关。使用靶向造影剂来获取以下信息的侵入性磁共振成像 (MRI) 方法该探针也将被设计用于帮助治疗。通过破坏疾病促进途径或药物输送进行干预。治疗能力还将促进纵向随访，以监测疾病进展和治疗我们将靶向分泌骨髓相关蛋白14（MRP-14，也称为S100A9）。来自活化的中性粒细胞、单核细胞和血小板，我们的数据表明 MRP-14 和 DVT 之间存在联系。 MRP-14 在 DVT 中呈高水平，在小鼠中敲除 MRP-14 可减弱 DVT 的形成。通过噬菌体文库组合方法，我们鉴定了以高特异性靶向 MRP-14 的特定肽配体我们将把 MRP-14 粘合剂与高分子 MRI 造影剂结合起来，并开发一种 MRI 协议用于非侵入性检测 MRP-14，以帮助 DVT 的诊断和预后。我们将开发一种有针对性的治疗方法：首先，我们将测试MRP-14功能是否受到破坏其次，我们将评估 MRP-14 溶栓药物的靶向递送。靶向治疗方法有可能克服出血风险：与治疗相关的疾病进展和治疗成功将通过纵向 MRI 进行评估。学习。