Imaging Vascular Phosphatidylethanolamine

血管成像磷脂酰乙醇胺

基本信息

批准号：
8324823
负责人：
Ming Zhao
金额：
$ 38.26万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-07 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8324823
关键词：
Address Affinity Anabolism Anticoagulants Antihypertensive Agents Arteries Autoantibodies Autoimmunity Binding Biological Markers Blood Blood Pressure Blood Vessels Cardiovascular system Cellular Membrane Curiosities Data Development Dimensions Disease Distal Elements Endothelial Cells Endothelium Functional disorder Gadolinium Goals Health Hemostatic function Human Hypertension Image Impairment In Vitro Knowledge Label Lead Light Link Literature Magnetic Resonance Imaging Masks Mechanics Mediating Metabolic Methodology Microscopic Modeling Modification Molecular Probes Mus Mutation N-terminal Normal Statistical Distribution Pathway interactions Patients Peptides Phosphatidylethanolamine Phospholipids Process Protein C Radiolabeled Rattus Reaction Regulation Resolution Risk Risk Factors Role Serum Signal Transduction Site Small Interfering RNA Source Specificity Spontaneous abortion Stimulus Stress Surface Thrombosis Time Tissues Treatment Efficacy Up-Regulation Vascular Diseases ascending aorta base biological systems duramycin extracellular gadolinium oxide hemodynamics immunoreactivity inhibitor/antagonist normotensive novel phosphatidylethanolamine public health relevance radiotracer response shear stress

项目摘要

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. PUBLIC HEALTH RELEVANCE: Phosphatidylethanolamine (PE) is an important anticoagulant in the circulatory system. The goal of this project is to characterize the distribution and dynamics of PE at the blood-endothelium surface using high-resolution, target-specific imaging. The findings will enhance our understanding in the regulation and impairment of hemostasis, which will lead to new imaging biomarkers for vascular health, anomalies and therapeutic efficacies.

描述（由申请人提供）：广泛的长期目标是表征在腔内皮表面的磷脂酰乙醇胺（PE），并为血管健康和疾病开发新的生物标志物。过去几十年来积累的证据表明，PE是一种重要的抗凝剂。但是，由于缺乏研究探针，PE在血内皮界面上的分布和动力学几乎是未知的。最近，我们开发了源自杜拉米霉素的PE特异性分子探针，这些探针具有高亲和力和高特异性。使用这些探针，获得了重要的初步数据以支持当前项目。首先，我们在主动脉流量分隔线的腔内皮表面和沿升主动脉的腔内皮表面上发现了非常高的PE。其次，这些血管区域也是抗PE（APE）自身免疫性的主要靶标，在猿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剪切应力时会上调表面PE，从而提示流动介导的调节机制。此外，我们记录了血液内皮界面处的PE在高血压中严重抑制，而不是正常的血管。鉴于初步数据，该项目的主要目标是更好地表征血管PE。提出了四个具体目的：1）合成和表征杜拉米霉素衍生的PE特异性分子探针，尤其是用于高分辨率，靶标特异性MRI的Gadolinium标记的T1药物。 2）探索内皮细胞中流介导的PE上调的机理，我们假设表面PE的调节受响应于剪切应力的机械传输过程的控制。 3）使用目标特异性MRI确定组织水平上血管PE的正态分布；我们假设腔内皮表面的PE水平与血液动力学应力程度相关。 4）使用各种大鼠高血压模型在高血压脉管系统中表征PE，并响应降压治疗。我们假设血管PE是与高血压相关的内皮功能障碍的标记。总体而言，在血内皮界面上有关PE的新知识将增强我们对止血的调节和损害的理解。反过来，这些有关血管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产生新的生物标志物。与公共卫生相关的是，PE的特征是脉管系统中一种关键的抗凝剂，将有助于我们了解内皮细胞循环血液对循环血的血栓性的调节。血管PE的动力学将提供有关血管疾病和血管疾病内皮功能障碍的重要信息。公共卫生相关性：磷脂酰乙醇胺（PE）是循环系统中的重要抗凝剂。该项目的目的是使用高分辨率，特异性的成像来表征PE在血内皮表面上的分布和动力学。这些发现将增强我们对止血的调节和损害的理解，这将导致新成像的血管健康，异常和治疗效率的生物标志物。