Research Interests

In vivo imaging of mouse development

Extensive genetic information and the rapidly expanding number of techniques available to manipulate the genome of the mouse have led to its widespread and increasing use in studies of development and to model human diseases. In this rapid proliferation of methods to genetically engineer mice, in vivo technologies to analyze anatomical structure and function in the mouse have not kept pace. The results of transgenic and gene targeting experiments, for the most part, are analyzed using histological methods which are static and two-dimensional, making it difficult to understand the underlying developmental and disease processes which are dynamic and three-dimensional. We are developing both ultrasound and magnetic resonance micro-imaging approaches to provide noninvasive, dynamic structural and functional data on developmental and disease processes in mice.

Ultrasound Biomicroscopy (UBM)
Ultrasound biomicroscopy (UBM) is a noninvasive, real-time, high resolution imaging technique that can be used to image mouse embryos and measure blood flow parameters over a wide range of early embryonic stages. UBM provides a unique approach to studying normal and abnormal development of the mouse brain, heart and other organs, in utero, at critical early stages of mouse embryogenesis. We have demonstrated the utility of UBM imaging and Doppler blood velocity measurements for analyzing cardiac development in the mouse from early embryonic through early postnatal stages, using UBM-derived indices of heart contractility and blood velocity waveforms to assess cardiovascular function, in normal and mutant mouse strains with putative defects in cardiovascular function, with the goal of providing new insights into structure / function relationships in the developing mammalian cardiovascular system.

We have developed a UBM image-guided injection system to introduce cells, viruses and other agents into a variety of mouse embryonic tissues over a wide range of early embryonic stages, to study cell lineages after in utero labeling with reporter-gene expressing retroviruses, and to study cell fate and migration after UBM-guided transplantation. In collaboration with the Fishell laboratory, we have also demonstrated the utility of gain-of-function studies using UBM-guided injections of high-titer retroviruses into specific embryonic tissues at predetermined time points. Current projects using this approach include injection of Sonic Hedgehog-expressing retrovirus into the early embryonic cerebellum to create a mouse model of a pediatric brain tumor, medulloblastoma.

Magnetic Resonance Micro-imaging (µMRI)
Magnetic resonance micro-imaging (µMRI) is a noninvasive imaging method that can be used to analyze brain and organ development and disease from early postnatal to adult stages, and with further development has the potential to image embryonic stages as well. The ability to obtain three-dimensional anatomical and functional image data with µMRI is providing the means to follow disease progression in several mouse models of human diseases. Longitudinal imaging studies are crucial to further understanding processes such as tumor progression and neuro-degeneration, since each animal presents a unique profile of disease progression. In these studies, we are focusing on the use of novel peptide- and antibody-labeled contrast agents to enhance specific cells/tissues on µMR images.