Genetically-engineered mice have been utilized widely for in vivo studies of vascular development and for studying vascular changes underlying pathogenesis in a wide range of human diseases such as stroke, cancer and ischemic heart disease. As a result, there is a critical need for in vivo methods to analyze dynamic changes in three-dimensional (3D) vascular morphology and gene expression patterns during development and disease in mouse models. To progress in this area, reporter mice are required for vascular imaging with more penetration than conventional optical microscopy. During the previous funding period, we established two novel reporter systems for ultrasound and magnetic resonance imaging (MRI), in vivo methods that can be used for high-resolution, 3D vascular imaging in developing and adult mice. Specifically, we developed a Biotag transgene for cell surface biotinylation, and generated Tie2-Biotag transgenic mice for targeted imaging of vascular endothelial cells (VECs) using avidinated contrast agents for both ultrasound and MRI. We also discovered that the Divalent Metal Transporter, DMT1 can be utilized as a highly effective reporter gene for Mn-enhanced MRI (MEMRI), an in vivo imaging method that has the potential for labeling both VECs and smooth muscle cells (SMCs), the two major vascular cell types. We now propose to take full advantage of these breakthroughs in molecular imaging technology, and to generate and validate the next generation universal reporter mice for imaging vascular morphologies and gene expression patterns from embryonic to adult stages. These reporter mice will be used to establish in vivo approaches for molecular imaging of the developing vasculature in wild type (WT) mouse embryos, and in Gli2-/- mutants, which we showed have patterning defects in the cerebral arteries. We will also utilize in vivo models of adult angiogenesis to test and validate the universal reporter mice.
The specific aims of the project are: 1) Optimize ultrasound and MRI protocols for vascular imaging from embryonic to adult stages; 2) Establish a universal Biotag reporter mouse for in vivo, multi-modality expression imaging of a variety of VEC genes; and 3) Establish a universal DMT1 reporter mouse for in vivo MEMRI imaging of both VECs and SMCs. This research will generate and validate universal reporter mice for in vivo vascular imaging with MRI and ultrasound, enabling unprecedented studies of dynamic changes in vascular morphologies and gene expression patterns, from embryonic to adult stages.
Genetically-engineered mouse models are widely used for studying the molecular and cellular basis of vascular abnormalities underlying a wide range of human diseases, including stroke, cancer and ischemic heart disease. To progress in this research, it is critical to develop effective in vivo methods to analyze the relationships between 3D gene expression and vascular morphologies. In this project, we will develop 3D ultrasound and MRI methods, combined with novel vascular reporter mice, enabling unprecedented studies of dynamic changes in vascular morphologies and gene expression patterns, from embryonic to adult stages.
| Zhang, Jiangyang; Wu, Dan; Turnbull, Daniel H (2018) In Utero MRI of Mouse Embryos. Methods Mol Biol 1718:285-296 |
| Suero-Abreu, Giselle A; Aristizábal, Orlando; Bartelle, Benjamin B et al. (2017) Multimodal Genetic Approach for Molecular Imaging of Vasculature in a Mouse Model of Melanoma. Mol Imaging Biol 19:203-214 |
| Ketterling, Jeffrey A; Aristizábal, Orlando; Yiu, Billy Y S et al. (2017) High-speed, high-frequency ultrasound, in utero vector-flow imaging of mouse embryos. Sci Rep 7:16658 |
| Phoon, Colin K L; Turnbull, Daniel H (2016) Cardiovascular Imaging in Mice. Curr Protoc Mouse Biol 6:15-38 |
| Suero-Abreu, Giselle A; Praveen Raju, G; Aristizábal, Orlando et al. (2014) In vivo Mn-enhanced MRI for early tumor detection and growth rate analysis in a mouse medulloblastoma model. Neoplasia 16:993-1006 |
| Bartelle, Benjamin B; Szulc, Kamila U; Suero-Abreu, Giselle A et al. (2013) Divalent metal transporter, DMT1: a novel MRI reporter protein. Magn Reson Med 70:842-50 |
| Aristizábal, Orlando; Mamou, Jonathan; Ketterling, Jeffrey A et al. (2013) High-throughput, high-frequency 3-D ultrasound for in utero analysis of embryonic mouse brain development. Ultrasound Med Biol 39:2321-32 |
| Parasoglou, Prodromos; Berrios-Otero, Cesar A; Nieman, Brian J et al. (2013) High-resolution MRI of early-stage mouse embryos. NMR Biomed 26:224-31 |
| Berrios-Otero, Cesar A; Nieman, Brian J; Parasoglou, Prodromos et al. (2012) In utero phenotyping of mouse embryonic vasculature with MRI. Magn Reson Med 67:251-7 |
| Bartelle, Benjamin B; Berríos-Otero, César A; Rodriguez, Joe J et al. (2012) Novel genetic approach for in vivo vascular imaging in mice. Circ Res 110:938-47 |
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