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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL102085-01
Application #
7861847
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Gao, Yunling
Project Start
2010-04-07
Project End
2015-03-31
Budget Start
2010-04-07
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$394,424
Indirect Cost
Name
Medical College of Wisconsin
Department
Biophysics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Hou, Songwang; Fölsch, Heike; Ke, Ke et al. (2017) Early endosome as a pathogenic target for antiphosphatidylethanolamine antibodies. Proc Natl Acad Sci U S A 114:13798-13803
Hou, Songwang; Harper, Paul E; Bardin, Nathalie et al. (2017) The outcome of ELISA for antiphosphatidylethanolamine antibodies is dependent on the composition of phosphatidylethanolamine. J Immunol Methods 440:27-34
Zang, Shiming; Shao, Guoqiang; Cui, Can et al. (2017) 68Ga-PSMA-11 PET/CT for prostate cancer staging and risk stratification in Chinese patients. Oncotarget 8:12247-12258
Luo, Rui; Niu, Lei; Qiu, Fan et al. (2016) Monitoring Apoptosis of Breast Cancer Xenograft After Paclitaxel Treatment With 99mTc-Labeled Duramycin SPECT/CT. Mol Imaging 15:
Ke, Ke; Strango, Zachariah I; Harper, Paul E et al. (2016) Influence of Phosphatidylethanolamine Concentration and Composition on the Detection of Antiphosphatidylethanolamine Antibodies by ELISA. J Clin Lab Anal 30:689-96
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Wang, Lei; Wang, Feng; Fang, Wei et al. (2015) The feasibility of imaging myocardial ischemic/reperfusion injury using (99m)Tc-labeled duramycin in a porcine model. Nucl Med Biol 42:198-204
Hou, Songwang; Grillo, Doris; Williams, Carol L et al. (2014) Membrane phospholipid redistribution in cancer micro-particles and implications in the recruitment of cationic protein factors. J Extracell Vesicles 3:
Zhang, Yuqing; Stevenson, Gail D; Barber, Christy et al. (2013) Imaging of rat cerebral ischemia-reperfusion injury using(99m)Tc-labeled duramycin. Nucl Med Biol 40:80-8
Johnson, Steven E; Li, Zhixin; Liu, Yu et al. (2013) Whole-body imaging of high-dose ionizing irradiation-induced tissue injuries using 99mTc-duramycin. J Nucl Med 54:1397-403

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