Recent advances in molecular cardiology have provided much insight into the genetic processes involved in normal heart development. Despite the proliferation of models of abnormal cardiovascular development, our ability to quantitatively characterize the physiology of the developing circulation has severely limited our mechanistic understanding of these targeted gene defects. The candidate's laboratory (PI: Daniel Turnbull, PhD) has developed a high-frequency, ultrasound device with Doppler capabilities that can noninvasively assess the developing cardiovascular system in early mouse embryos, the animal model of choice for studying mammalian development. Our laboratory has begun preliminary studies using echocardiography to study the embryonic circulation of the mouse in a quantitative manner. This noninvasive approach perturbs the circulation less than traditional invasive techniques, thus resulting in the acquisition of more physiologically relevant data. The following questions are being asked: 1) what are the blood flow patterns in the normal developing circulation, 2) at each developmental stage to be studied, how responsive are the heart and vascular bed to pharmacological manipulation of cardiac contractility and vascular tone, 3) what changes in cardiac function and blood flow patterns occur in mice with cardiomyopathies and what are the mechanisms leading to embryonic lethality, and 4) how responsive are cardiomyopathic mice to pharmacological manipulation of cardiac contractility and vascular tone? These questions have broad implications for understanding developmental cardiovascular function in the both normal and abnormal embryo. With a better understanding of cardiovascular development and some of the mechanisms underlying congenital heart disease, treatment of congenital heart disease may eventually become possible even as early as embryonic life and may even serve to reverse abnormal developmental mechanisms, allowing normal heart development.
