In basic cardiac research, application of an electrical pacing lead to cardiac tissues is invasive and can cause tissue damages. It remains a challenge to develop novel pacing and cardioversion strategies and to evaluate their chronic effects non-invasively in the heart's innate physiological environment. As a promising alternative to electrical pacing, optical pacing does not require contact, has high spatial and temporal precision, is more specific and avoids artifacts in electrical stimulation. Recent developments in the field of optogenetics make it possible for non-invasive and specific optical control of the heart rhythm in animal models, such as in Drosophila melanogaster. Drosophila is a powerful genetic model system that has been used since the early 1900s to characterize genes associated with human diseases, including cardiac diseases. About 80% of human diseases in which the disease-related gene has been identified have an orthologue in Drosophila. Thus, studies performed in Drosophila can provide general insights into conserved mechanisms of pacing in cardiac development, which can be applied to higher organisms including humans. Anatomically, the Drosophila heart tube is located on the dorsal side of its abdomen, within only 200 m from the tissue surface. This makes Drosophila an ideal model system to take advantages of existing optogenetic toolbox and emerging non-invasive imaging technologies such as optical coherence tomography (OCT) and optical coherence microscopy (OCM) to control and evaluate the Drosophila heart function using light non-invasively. Working in collaboration with Drs. Airong Li and Rudolph E. Tanzi from the Massachusetts General Hospital, we propose: 1) to further develop and optimize an integrated optical imaging and pacing apparatus to enable new functionalities and high-throughput measurements; 2) to develop double transgenic Drosophila models and optimize experimental protocols for non-invasive optogenetic pacing of the Drosophila heart; and 3) to determine the influence of non-invasive optogenetic pacing on heart development in Drosophila with normal cardiac function and cardiac dysfunctions. The non-invasive optical pacing and imaging platform, combined with transgenic Drosophila models, will enable us to perform a series of new experiments in developmental cardiology, which can provide insights into conserved molecular and genetic mechanisms of the pacing effects on heart development and arrhythmias. This offers great potential in developing new therapeutic pacing strategies to treat arrhythmias. The proposed Academic Research Enhancement Award (AREA) program will not only serve the need for cutting-edge research but also aim at training undergraduate and graduate students to work at the interface of engineering and biological sciences and stimulate their interest in pursuing a career in biomedical research.
We will develop an integrated non-invasive optical imaging and pacing platform and transgenic fruit fly models to study conserved mechanisms of the pacing effects on heart development and arrhythmias. The proposed program will also serve the need for training undergraduate and graduate students to work at the interface of engineering and biological sciences and stimulate their interest in pursuing a career in biomedical research.
