Novel optical imaging and pacing platform for developmental cardiology

 描述：在基础心脏研究中，对心脏组织应用电子起搏是有侵入性的，可能会导致组织损伤。开发新的起搏和复律策略，并在心脏固有的生理环境中无创地评估其慢性影响，仍然是一个挑战。光学起搏作为电起搏的一种很有前途的替代方法，不需要接触，具有较高的时空精度，更具特异性，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中对心率进行非侵入性和特异性的光学控制成为可能，例如在果蝇身上。果蝇是一种强大的遗传模型系统，自20世纪初以来一直被用来描述与人类疾病相关的基因，包括心脏病。在已确定与疾病相关的基因的人类疾病中，约80%在果蝇中有同源基因。因此，在果蝇身上进行的研究可以为心脏发育中起搏的保守机制提供一般性的见解，这可以应用于包括人类在内的高等生物。从解剖学上讲，果蝇的心管位于其腹部的背侧，距离组织表面只有200微米。这使得果蝇成为一种理想的模型系统，可以利用现有的光遗传工具箱和新兴的光学相干断层扫描(OCT)和光学相干显微镜(OCM)等非侵入性成像技术来无创性地利用光来控制和评估果蝇的心脏功能。我们与马萨诸塞州总医院的李艾荣博士和鲁道夫·E·坦齐博士合作，建议：1)进一步开发和优化集成光学成像和起搏设备，以实现新功能和高通量测量；2)建立双转基因果蝇模型，并优化果蝇心脏无创性光基因起搏的实验方案；3)确定无创光基因起搏对心功能正常和心脏功能障碍果蝇心脏发育的影响。无创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，从而为研究起搏对心脏发育和心律失常影响的保守分子和遗传机制提供见解。这为开发治疗心律失常的新的治疗性起搏策略提供了巨大的潜力。拟议的学术研究促进奖(AREA)计划不仅服务于尖端研究的需要，而且旨在培养本科生和研究生在工程和生物科学的交界处工作，并激发他们从事生物医学研究的兴趣。

 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.