Imaging Vascular Phosphatidylethanolamine

描述(由申请人提供)：广泛的、长期的目标是表征管腔内皮表面的磷脂酰乙醇胺(PE)，并开发用于血管健康和疾病的新的生物标记物。过去几十年的积累证据表明，PE是一种重要的抗凝血剂。然而，由于缺乏探索性的研究，PE在血液-内皮界面的分布和动态仍然是未知的。最近，我们开发了来源于杜拉霉素的PE特异性分子探针，它与PE具有高亲和力和高特异性。利用这些探测器，获得了支持当前项目的重要初步数据。首先，我们发现在主动脉血流分离器的管腔内皮表面和沿升主动脉的PE水平非常高。其次，这些血管区域也是抗PE(APE)自身免疫的主要靶点，在APE和特发性血栓形成之间提供了物理联系。此外，培养的内皮细胞在受到剪切力时上调表面PE，从而暗示了一种流动介导的调节机制。此外，我们还发现，与血压正常的血管相比，高血压患者血管-血管内皮细胞界面的PE受到严重抑制。根据初步数据，本项目的主要目标是更好地描述血管PE的特征。提出了四个具体的目标：1)合成和表征杜拉霉素衍生的PE特异性分子探针，特别是用于高分辨率、靶向性磁共振成像的Gd标记T1试剂。2)探讨血流介导的内皮细胞PE上调的机制，其中我们假设表面PE的调节是由一个响应切应力的机械转导过程控制的。3)利用靶点特异性MRI确定血管内皮细胞在组织水平上的正态分布；我们假设血管内皮细胞表面的PE水平与血流动力学应力的程度相关。4)使用不同的高血压大鼠模型和对降压治疗的反应来表征高血压血管中的PE。我们假设血管PE是与高血压相关的内皮功能障碍的标志。总体而言，关于血管内皮细胞界面PE的新知识将加强我们对止血的调节和损害的理解。反过来，这些关于血管内皮细胞动力学的发现将为血管内皮细胞健康以及血管异常的进展和治疗带来新的生物标志物。PE作为血管系统中一种重要的抗凝剂，其特性将有助于我们理解内皮对循环血液血栓形成潜力的调节。血管内皮细胞的动力学变化将为血管疾病中的血栓形成和内皮功能障碍提供重要信息。

DESCRIPTION (provided by applicant): The broad, long-term objective is to characterize phosphatidylethanolamine (PE) at the luminal endothelial surface, and develop new biomarkers for vascular health and diseases. Accumulating evidence from past decades demonstrates that PE is an important anticoagulant. However, the distribution and dynamics of PE at the blood-endothelium interface remain virtually unknown due to a lack of investigative probes. Recently, we developed PE-specific molecular probes derived from Duramycin, which bind PE with high affinity and high specificity. Using these probes, important preliminary data were obtained in support of the current project. First, we discovered an extraordinarily high level of PE at the luminal endothelial surface of aortic flow dividers and along the ascending aorta. Second, these vascular regions are also the primary targets for anti-PE (aPE) autoimmunity, providing a physical link between aPE and idiopathic thrombosis. In addition, cultured endothelial cells upregulate surface PE when subject to shear stress, thereby suggesting a flow-mediated regulatory mechanism. Furthermore, we documented that PE at the blood-endothelium interface is severely suppressed in hypertensive, as opposed to normotensive, vessels. In light of the preliminary data, the primary goal of this project is to better characterize vascular PE. Four Specific Aims are proposed to: 1) Synthesize and characterize Duramycin-derived PE-specific molecular probes, in particular, the gadolinium-labeled T1 agents for high-resolution, target-specific MRI. 2) Explore the mechanism of flow-mediated PE upregulation in endothelial cells, where we hypothesize that the modulation of surface PE is governed by a mechanotransduction process in response to shear stress. 3) Determine the normal distribution profile of vascular PE on a tissue level using target-specific MRI; we hypothesize that the level of PE at the luminal endothelial surface correlates with the degree of hemodynamic stress. 4) Characterize PE in hypertensive vasculature using various rat models of hypertension and in response to antihypertensive therapies. We hypothesize that the vascular PE is a marker for endothelial dysfunction associated with hypertension. Overall, new knowledge about PE at the blood-endothelium interface will enhance our understanding of the regulation and impairment of hemostasis. In turn, these discoveries regarding the dynamics of vascular PE will give rise to new biomarkers for endothelial health, and the progression and treatments of vascular anomalies. RELEVANCE TO PUBLIC HEALTH The characterization of PE, as a critical anticoagulant in the vasculature, will help us understand the modulation of the thrombotic potential of the circulating blood by the endothelium. The dynamics of vascular PE will provide important information regarding the thrombotic disorders and endothelial dysfunction in vascular diseases.