Imaging Vascular Phosphatidylethanolamine

血管成像磷脂酰乙醇胺

基本信息

批准号：
7861847
负责人：
Ming Zhao
金额：
$ 39.44万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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/7861847
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 Public Health 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 abstracting ascending aorta base biological systems duramycin extracellular 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生物标志物。过去几十年积累的证据表明，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态实际上仍然未知。最近，我们开发了源自耐久霉素的PE特异性分子探针，它以高亲和力和高特异性结合PE。使用这些探针，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升主动脉发现了异常高水平的 PE。其次，这些血管区域也是抗 PE (aPE) 自身免疫的主要目标，提供了 aPE 和特发性血栓形成之间的物理联系。此外，培养的内皮细胞在受到剪切应力时上调表面PE，从而表明存在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，高血压血管中血液-内皮界面的 PE 受到严重抑制。根据初步数据，该项目的主要目标是更好地表征血管性肺栓塞。提出了四个具体目标： 1) 合成和表征耐久霉素衍生的 PE 特异性分子探针，特别是用于高分辨率、目标特异性 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，我们假设表面PE的调节是由响应剪切应力的机械转导过程控制的。 3) 使用目标特异性 MRI 确定组织水平上血管 PE 的正态分布曲线；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和对抗高血压治疗的反应来表征高血压脉管系统中的 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物。总体而言，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害的理解。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。与公众健康的相关性 PE 作为脉管系统中重要的抗凝剂，其特性将帮助我们了解内皮细胞对循环血液血栓形成潜力的调节。血管PE的动态变化将为血管疾病中血栓性疾病和内皮功能障碍提供重要信息。公共卫生相关性：磷脂酰乙醇胺 (PE) 是循环系统中重要的抗凝剂。该项目的目标是利用高分辨率、目标特异性成像来表征血液内皮表面 PE 的分布和动态。这些发现将增强我们对止血调节和损伤的理解，从而产生用于血管健康、异常和治疗效果的新的成像生物标志物。