Imaging Vascular Phosphatidylethanolamine

描述（由申请方提供）：广泛的长期目标是表征管腔内皮表面的磷脂酰乙醇胺（PE），并开发血管健康和疾病的新生物标志物。过去几十年来积累的证据表明，PE是一种重要的抗凝剂。然而，由于缺乏研究探针，PE在血液-内皮界面的分布和动力学仍然几乎未知。最近，我们开发了衍生自Duramycin的PE特异性分子探针，其以高亲和力和高特异性结合PE。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，我们在主动脉分流器的管腔内皮表面和沿着升主动脉发现了非常高水平的PE。其次，这些血管区域也是抗PE（aPE）自身免疫的主要靶点，提供了aPE和特发性血栓形成之间的物理联系。此外，培养的内皮细胞上调表面PE时，受到剪切应力，从而表明流量介导的调节机制。此外，我们证明，PE在血液内皮界面是严重抑制高血压，而不是血压正常，血管。根据初步数据，本项目的主要目标是更好地表征血管PE。提出了四个具体目标：1）合成和表征Duramycin衍生的PE特异性分子探针，特别是用于高分辨率，靶向特异性MRI的钆标记T1试剂。2)探索内皮细胞中流动介导的PE上调的机制，其中我们假设表面PE的调制是由响应于剪切应力的机械转导过程控制的。3)使用靶向特异性MRI确定组织水平上血管PE的正态分布特征;我们假设管腔内皮表面的PE水平与血流动力学应激程度相关。4)使用各种高血压大鼠模型表征高血压血管系统中的PE，以及对抗高血压治疗的反应。我们假设血管PE是高血压相关内皮功能障碍的标志物。总的来说，关于血液-内皮界面PE的新知识将增强我们对止血调节和损伤的理解。反过来，这些关于血管PE动力学的发现将为内皮健康以及血管异常的进展和治疗带来新的生物标志物。与公共卫生的相关性PE作为血管系统中的关键抗凝剂，其特征将帮助我们了解内皮对循环血液血栓形成潜力的调节。血管PE的动力学研究将为血管疾病的血栓性疾病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.