Using mice as models to study developmental physiology and human disease

A major goal of our lab is to generate powerful and accessible tools for evaluating physiologic function in genetically-altered mice (www.mshri.on.ca/adamsonlab).  We use a state-of-the-art high resolution ultrasound system known as the Ultrasound Biomicroscope to monitor morphology and hemodynamics from implantation to adulthood in mice. Our lab has a longstanding interest in cardiovascular hemodynamic development in general, and in the role of the placenta in controlling maternal and fetal hemodynamic function during pregnancy in particular.  All work has ethical approval and is conducted in accordance with the guidelines of the Canadian Council on Animal Care (www.ccac.ca).  Our current work investigates the feasibility and tremendous potential of using genetically-altered mice to explore the mechanisms controlling normal physiological development and the mechanisms leading to disease. 

Cardiovascular and Placental Physiology During Pregnancy
Using large animals and computer models, we showed that elevated vascular resistance in the feto-placental microvasculature and/or venous outflow tract most likely causes the highly pulsatile blood velocity waveforms commonly observed in the umbilical arteries of human fetuses with intrauterine growth restriction.  We are now using high frequency ultrasound to monitor umbilical arterial velocity waveforms in mouse embryos.  We also use micro-computed tomography to evaluate placental vascularization during pregnancy in normal and mutant mice in collaboration with Dr. John Sled.  Similar methods are being used to simultaneously evaluate cardiovascular function in the maternal circulation during pregnancy.  The goal of this work is to determine the developmental mechanisms responsible for abnormal placental hemodynamics and the impact on fetal growth and development, and on maternal cardiovascular adaptations to pregnancy. Ultimately, this work will advance our understanding of two of the most common and serious complications of human pregnancy, fetal intrauterine growth restriction and maternal preeclampsia.

High Resolution Ultrasound Imaging and Doppler Assessment in Mice
We use the ultrasound biomicroscope developed by Dr. Stuart Foster and commercialized by VisualSonics.   The ultrasound biomicroscope generates high resolution real-time images of living embryos in utero, and detects strong blood flow (Doppler) signals even from tiny embryonic mouse hearts <1 mm in size.  We have shown that echocardiographic exams similar to those performed clinically are now possible on embryos, neonates and adult mice.  Furthermore, we have found that the ultrasound biomicroscope can be used to guide fine-tipped cannulae into precise locations within the developing conceptus as young as 6.5 d gestation (2 days postimplantation), and to inject nl volumes into targets only 200 μm in size. We are using these methods to develop treatments to promote optimal growth and development of the fetus and placenta. In complicated human pregnancies, we hope these treatments will one day lead to the birth of healthier babies with brighter futures.

Evaluation of Cardiovascular Function In Vivo in Mice During Pre- and Postnatal Development
Genetic mouse models have yielded remarkable insights into the gene products that control embryonic cardiovascular development, and have proven useful as models of human disease because mice often display similar cardiovascular pathology when human genetic mutations are replicated.  Disrupting important cardiovascular genes often has marked consequences on cardiovascular structure and function in embryos, fetuses, and neonates.  Indeed, it is often necessary to establish the phenotype in embryos or neonates because most or all may die before adulthood or even before birth.  However, technology to assess murine cardiovascular function in utero, when body size is only a few mm, is very limited.

Thus, our long-term goal is to develop a broad repertoire of techniques to quantitatively evaluate cardiovascular development and function during prenatal and postnatal development in mice and, in the future, to develop methods to administer gene or cell based therapies in utero.  Our emphasis is on non-invasive tools and tools that parallel those used clinically.  This emphasis is to facilitate longitudinal studies and to maximize the clinical relevance of mutant mice as models for human disease.

Physiological Testing of Mutant Mouse Models of Human Disease
Powerful techniques for genetic manipulation in the mouse have led to unparalleled progress in the task of assigning function to the ~30,000 genes of the mammalian genome. A major goal of our lab is to generate equally powerful and accessible tools for evaluating physiologic function in mice in order to accelerate this task. In the Centre for Modeling Human Disease (CMHD) Mouse Physiology Laboratory at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital (www.cmhd.ca), we perform high-throughput tests for cardiovascular, renal, skeletal, and hematologic function to identify new genes that may underlie important human diseases in the CMHD’s random mutagenesis screen. Such tests are also being used to characterize mice with targeted mutations, as well as normal mice throughout development and pregnancy. Our research lab exploits recent progress in high frequency ultrasound systems to monitor morphology and hemodynamics from implantation to adulthood in mutant mice generated by random mutagenesis or in the research labs of our collaborators.

Graduate Students:

• Monique Rene

Selected References: