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。

• 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
• 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

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.

摘要 数据显示，每年有6万至10万美国人死于静脉血栓栓塞症(VTE)， 50%的存活患者会有长期的并发症，约三分之一的幸存者会有 10年内复发。美国的医疗费用令人震惊，治疗糖尿病的负担很高 VTE患者；据估计，每年花费100亿美元用于治疗和人力- 职业技术教育的管理。对静脉血栓栓塞症，特别是深静脉血栓栓塞症的临床诊断，尤其是对深静脉血栓的准确诊断是非常必要的 血栓形成(DVT)，以及减少安全问题的针对性治疗，特别是颅内出血，以及 与溶栓药物有关。目前的诊断方法不准确：血液检测评估D-二聚体 血液水平只是深静脉血栓的征兆。X-射线静脉造影和超声检查等成像技术 反映静脉解剖的变化，但这些模式不提供关于分子的信息 血栓的成分。只有活组织检查和组织学检查才能提供所需的分子信息。 预后，但这些方法是侵入性的，并与重大风险相关。我们提出了一个非- 使用靶向造影剂的有创磁共振成像(MRI)方法获得 血栓的分子组成有助于预后。该探头还将被设计成帮助治疗- 通过扰乱致病途径或药物输送进行预防。集成成像和 治疗能力还将促进纵向跟踪，以监测疾病进展和治疗 成功。我们将以髓系相关蛋白14(MRP-14，也称为S100A9)为靶点。MRP-14被分泌出来 来自激活的中性粒细胞、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。 在DVT中发现高水平的MRP-14，在小鼠中敲除MRP-14可减少DVT的形成。使用 通过噬菌体文库组合的方法，我们鉴定了针对MRP-14的高特异性多肽配体。 真是天真。我们将把MRP-14结合剂与一种大分子磁共振造影剂整合在一起，我们将开发一种 MRI无创检测MRP-14有助于DVT的诊断和预后。同时， 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功能的中断 可以抑制深静脉血栓的形成。第二，我们将评估MRP-14溶栓药物Plas-14的靶向递送。 纤溶酶原激活剂(TPA)靶向治疗方法具有克服出血风险的潜力，因为- 与治疗联系在一起。疾病进展和治疗成功将在纵向核磁共振中进行评估。 学习。