Novel optical imaging and pacing platform for developmental cardiology

 描述：在基础心脏研究中，将电起搏电极导线应用于心脏组织是有创的，可能导致组织损伤。它仍然是一个挑战，开发新的起搏和心脏复律策略，并评估其在心脏的先天生理环境中的慢性影响非侵入性。作为电起搏的一种有前途的替代方案，光学起搏不需要接触，具有高的空间和时间精度，更具体，避免了电刺激中的伪影。光遗传学领域的最新发展使得在动物模型（例如黑腹果蝇（Drosophila melanogaster））中对心律进行非侵入性和特异性光学控制成为可能。果蝇是一种强大的遗传模型系统，自20世纪初以来一直用于表征与人类疾病（包括心脏病）相关的基因。大约80%的人类疾病，其中疾病相关基因已被确定在果蝇中有直系同源物。因此，在果蝇中进行的研究可以提供心脏发育中保守的起搏机制的一般见解，这可以应用于包括人类在内的高等生物。在解剖学上，果蝇的心管位于其腹部的背侧，距离组织表面仅200 µm。这使得果蝇成为一个理想的模型系统，可以利用现有的光遗传工具箱和新兴的非侵入性成像技术，如光学相干断层扫描（OCT）和光学相干显微镜（OCM），使用光非侵入性地控制和评估果蝇心脏功能。与李爱荣博士和鲁道夫·E. Tanzi的研究成果，我们提出：1）进一步开发和优化集成光学成像和起搏设备，以实现新的功能和高通量测量; 2）开发双转基因果蝇模型，优化果蝇心脏非侵入性光遗传起搏的实验方案;（3）研究无创性光遗传起搏对心功能正常和心功能不全果蝇心脏发育的影响。非侵入性光学起搏和成像平台与转基因果蝇模型相结合，将使我们能够在发育心脏病学中进行一系列新的实验，这些实验可以深入了解起搏对心脏发育和心律失常影响的保守分子和遗传机制。这为开发新的治疗性起搏策略来治疗心律失常提供了巨大的潜力。拟议的学术研究促进奖（AREA）计划不仅将满足尖端研究的需要，还旨在培养本科生和研究生在工程和生物科学的接口工作，并激发他们在生物医学研究中追求职业生涯的兴趣。

 DESCRIPTION: 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 µm 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.