Over the past decade, investigations using genetically-engineered mice have led to new insights into the genetic control of embryonic vascular development, which has also had a major impact on our understanding of neovascularization in many human diseases including cancer, atherosclerosis and diabetes. Micro-imaging methods such as ultrasound biomicroscopy (UBM) and magnetic resonance micro-imaging (micro-MRI) can play an important role in this research, enabling direct in utero visualization of the developing mouse embryo. To date, there has been relatively little progress in the area of molecular imaging with ultrasound and MRI, especially in the area of vascular development. UBM is a real time imaging method enabling noninvasive in vivo analysis of mouse embryonic cardiovascular anatomy and hemodynamics, and can also be applied for image-guided intravascular injection of contrast agents. Micro-MRI provides better 3D resolution and more flexibility than UBM in manipulating cellular/tissue contrast, including more available contrast agents and approaches for cell-targeted imaging, but requires longer acquisition times, and has only recently been demonstrated for effective in utero imaging of mouse embryos. Several reports have recently demonstrated that biotinylation of cell surfaces can be achieved, allowing cell-targeted imaging with avidin-conjugated contrast agents, which are now available for both ultrasound and MRI. This is an attractive option for imaging vascular endothelial cells (VECs), since contrast agents can be delivered to the cells of interest via intravascular injection, even at embryonic stages of development. Moreover, the binding between avidin and biotin is the strongest found in nature, which should make it possible to label vascular cells even in the face of high wall shear rates associated with arterial blood flow.
The specific aims of this project are: 1) To optimize the micro-MRI protocols required for in utero analysis of cardiovascular development;2) To produce transgenic mice designed for targeted imaging of VECs with UBM and micro-MRI;and 3) To establish VEC-targeted micro-MRI approaches for improved analyses of embryonic vasculature. The approaches developed in this project will provide powerful new tools for direct analysis of vascular development in living mouse embryos. Significantly, these new molecular imaging methods will provide, for the first time, the ability to detect vascular gene expression in utero in normal and genetically-engineered mice.

Public Health Relevance

This project aims to move ultrasound and MRI vascular micro-imaging methods beyond measures of anatomy and function, to the level of in vivo molecular imaging in genetically-engineered mouse models of a wide range of cardiovascular disease. These new molecular imaging approaches will revolutionize mouse genetics, enabling new studies linking gene expression to vascular morphology and physiological function in the best characterized mammalian model of human development and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078665-07
Application #
8197464
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Buxton, Denis B
Project Start
2004-09-22
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$419,513
Indirect Cost
$172,013
Name
New York University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Aristizabal, Orlando; Mamou, Jonathan; Turnbull, Daniel H et al. (2009) Doppler-derived trigger signals for high-frame-rate mouse cardiovascular imaging. Conf Proc IEEE Eng Med Biol Soc 2009:1987-90
Berrios-Otero, Cesar A; Wadghiri, Youssef Zaim; Nieman, Brian J et al. (2009) Three-dimensional micro-MRI analysis of cerebral artery development in mouse embryos. Magn Reson Med 62:1431-9
Nieman, Brian J; Szulc, Kamila U; Turnbull, Daniel H (2009) Three-dimensional, in vivo MRI with self-gating and image coregistration in the mouse. Magn Reson Med 61:1148-57
Deans, Abby E; Wadghiri, Youssef Zaim; Berrios-Otero, Cesar A et al. (2008) Mn enhancement and respiratory gating for in utero MRI of the embryonic mouse central nervous system. Magn Reson Med 59:1320-8
Ketterling, Jeffrey A; Mamou, Jonathan; Allen 3rd, John S et al. (2007) Excitation of polymer-shelled contrast agents with high-frequency ultrasound. J Acoust Soc Am 121:EL48-53

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