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

总结 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%的幸存者会有长期并发症，约三分之一的幸存者有 10年内复发。美国的医疗保健费用是惊人的，并进行了高负担的治疗， 静脉血栓栓塞患者;据估计，每年花费100亿美元用于治疗和治疗， 职业性肺栓塞。目前迫切需要对静脉血栓栓塞，特别是深静脉血栓栓塞进行准确的临床诊断 血栓形成（DVT）和靶向治疗，以减少安全性问题，特别是颅内出血， 与血栓溶解药物有关。目前的诊断方法不准确：血液检查评估D-二聚体 血液中的浓度只能说明深静脉血栓X线静脉造影和超声检查等成像技术 反映了静脉解剖结构的变化，但这些模式不提供有关分子的信息， 血栓的成分。只有活检后的组织学才能提供ac所需的分子信息。 虽然这些方法具有良好的预后，但这些方法是侵入性的，并且与显著的风险相关。我们提出一个非- 一种使用靶向造影剂的侵入性磁共振成像（MRI）方法， 血栓分子组成，以帮助预后。该探针还将被设计用于帮助治疗- 通过破坏疾病促进途径或药物递送来进行干预。集成成像和 治疗能力还将促进纵向随访，以监测疾病进展和治疗 成功我们将靶向骨髓相关蛋白14（MRP-14，也称为S100 A9）。MRP-14被分泌 从活化的中性粒细胞、单核细胞和血小板，我们的数据表明MRP-14和DVT之间的联系。 MRP-14在DVT中被发现处于高水平，并且在小鼠中敲除MRP-14减弱DVT形成。使用 通过噬菌体文库组合方法，我们鉴定了特异性肽配体，其以高特异性靶向MRP-14， ficity。我们将把MRP-14结合剂与大分子MRI造影剂结合， MRI方案用于MRP-14的非侵入性检测，以辅助DVT的诊断和预后。与此同时， 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功能的破坏是否 可以减少DVT的形成。第二，我们将评估MRP-14靶向递送溶栓药物plas， minogen activator（tPA）。靶向治疗方法具有克服出血风险的潜力，因为- 与治疗有关。将在纵向MRI中评价疾病进展和治疗成功率 study.

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.