Development of new NIR probes to study human cardiac excitation

描述(申请者提供)：这个项目是纽约州立大学北部医科大学和立陶宛考纳斯医科大学的合作项目。合作的目标是将新的光学成像技术扩展到人类组织，以可视化心脏的电活动，并探索其临床应用的潜力。该项目是生物工程研究伙伴关系赠款(NIH补助金编号5R01HL07163501)的延伸，涉及纽约州立大学北部医科大学的A.Pertsov博士(PI)、马萨诸塞州综合医院核磁共振中心的D.Boas博士、康涅狄格大学健康中心的L.Loew博士(Co-PI)和哈佛大学的D.Weitz博士(Co-PI)的研究小组。这项新技术将利用扩散光学层析成像和新型近红外(NIR)电压敏感染料。该项目的具体目标是：(I)测量人体心脏组织的光学性质，如吸收和散射，这是解决正向问题(重建的关键要素)所必需的。研究新型苯乙烯基近红外电压敏感染料的特性(膜结合和电压敏感性)。为人体研究优化激发/发射滤光片和染料负载方案；(Ii)评估电压敏感染料对人体心肌细胞和心脏组织的急性毒性和光毒性；(Iii)对激发波在人体心脏组织和异体心脏组织中的传播进行初步光学标测研究。这项拟议的研究将通过提供有关近红外电压敏感染料在人体心脏组织中的性能的独特知识，使美国的心脏研究受益。通过与美国的合作，立陶宛将建立第一个光学测绘系统。立陶宛的合作者将接受最先进的光学测绘技术方面的培训，从而促进立陶宛的心脏研究。总之，成功的合作将导致开发一种新的心脏成像技术，这是其临床应用的第一步。这也将为进一步开展互利的国际合作提供坚实的基础。公共卫生相关性：危险心律失常的治疗依赖于对心肌病理区域的准确电生理识别(标测)，随后使用射频消融将其移除。这项国际合作旨在探索一种利用近红外荧光电压敏感分子探针的新测绘技术，该分子探针结合到细胞膜上，并根据膜电位改变荧光。这项新技术通过提高分辨率和加快消融目标的识别，应该比利用电子记录的传统测绘具有显着优势。

DESCRIPTION (provided by applicant): This project is a collaboration between SUNY Upstate Medical University and Kaunas Medical University, Lithuania. The goal of the collaboration is to extend to human tissues novel optical imaging techniques for visualization of electrical activity in the heart and to explore its potential for clinical applications. This project is an extension of a partnership grant in Bioengineering Research (NIH Grant No. 5R01HL07163501) involving the research groups of Dr. A. Pertsov (PI) at SUNY Upstate Medical University, Dr. D. Boas at the Massachusetts General Hospital NMR Center, Dr. L. Loew at the University of Connecticut Health Center (Co-PI), and the group of Dr. D. Weitz at Harvard University (Co-PI). The new technology will utilize diffusive optical tomography and novel near infrared (NIR) voltage-sensitive dyes. The specific aims of the project are: (i) To measure optical properties of human cardiac tissues, such as absorption and scattering, necessary for solving the forward problem (key element of the reconstruction). To study characteristics (membrane binding and voltage sensitivity) of novel styryl NIR voltage-sensitive dyes with optimized lipophilic tails in human cardiac myocytes/tissues. To optimize excitation/emission filters and dye loading protocols for human studies; (ii) To assess any acute toxicity and phototoxicity of voltage-sensitive dyes in isolated human cardiac myocytes and in cardiac tissue; (iii) To conduct pilot optical mapping studies of excitation wave propagation in isolated human cardiac tissue and explanted heart. The proposed study will benefit US cardiac research by providing unique knowledge about the performance of NIR voltage-sensitive dyes in human cardiac tissues. By having a collaboration with the US, the first optical mapping system in Lithuania will be built. Lithuanian collaborators will be trained in state-of-the-art optical mapping techniques, thus advancing Lithuanian cardiac research. In conclusion, a successful collaboration will result in the development of a novel cardiac imaging technology, the first step towards its clinical application. It will also provide a solid basis for further mutually beneficial international cooperation. PUBLIC HEALTH RELEVANCE: The treatment of dangerous cardiac arrhythmias relies on accurate electrophysiological identification (mapping) of pathological regions of myocardium that are subsequently removed using radio- frequency ablation. This international collaboration is intended to explore a new mapping technology utilizing near-infrared fluorescent voltage-sensitive molecular probes, which bind to cell membranes and change fluorescence according to membrane potential. The new technology should have a significant advantage over conventional mapping utilizing electrical recordings by increasing the resolution and speeding up the identification of ablation targets.