Retinal Nanophotoswitch

建议：1404089PI：Humayun，Mark S.标题：视网膜纳米光开关意义拟议研究的目标是开发一种新型的神经光子分子开关，用于神经元的光激活。基于这种纳米开关(NPS)的视觉假体有可能提高数百万患有视网膜退行性疾病的患者的视力，例如视网膜色素变性和老年性黄斑变性。这项建议很有新意。生物物理机制完全不同于电子设备和其他基于分子光开关的方法。除了视力恢复，它通常是一种控制可兴奋细胞的有用方法。如果成功，它可能会对目前治疗效果不佳的患者产生巨大影响。跨学科研究为参与研究的研究生和本科生提供了极好的教育机会。提出建议的团队在将女性、代表性不足的少数族裔和本科生纳入他们的研究方面有着非凡的记录。他们在接触当地社区方面也有良好的记录，计划的外展活动包括为教师提供研究经验和为K-12学生提供活动。技术描述纳米光开关(NPS)为体外和潜在的体内神经元功能的基础科学研究提供了一种新的工具来激发电活动。这一假设是基于NPS的设计和先导实验的结果，即光在NPS中诱导一个电偶极子。初步数据表明，基于联吡啶(Rubpy)的核糖核酸(NPS)插入细胞膜，在可见光照射下，在培养的可兴奋细胞和大鼠视网膜上触发动作电位。当注射到失明感光细胞退化大鼠的眼内时，视觉刺激诱导上丘的电活动。研究还表明，NPS既可以使膜去极化，也可以使膜超极化，这取决于环境氧化还原电位。这种在一个生物光子开关中双向调节膜电位的独特组合提供了激活和抑制具有相同分子的受照细胞的动作电位激发的能力，从而在很大程度上增加了神经元控制的灵活性。NPS将有助于研究任何可电兴奋的细胞，例如，包括心肌细胞、平滑肌细胞、神经内分泌细胞以及某些神经胶质细胞和癌细胞。由于光激活的信号单位是单个神经元，因此基于NPS系统的视觉假体有可能为数百万因视网膜退行性疾病(如视网膜色素变性(RP)和老年性黄斑变性(AMD))而导致的光感受器丧失的患者提供更高的视力。与其他使用光遗传学或基于偶氮苯的光开关的纳米级光细胞调制方法不同，由于NPS独特的光-电信号转导机制，这种方法不需要基因操作、有毒的紫外线照射或免疫原性分子。

Proposal: 1404089PI: Humayun, Mark S.Title: Retinal NanophotoswitchSignificance The objective of the proposed research is to develop a novel neurophotonic molecular switch for light-activation of neurons. A visual prosthesis based on this nanophotoswitch (NPS) has the potential to improve the visual acuity for the millions of patients suffering from retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration. This proposal is very innovative. The biophysical mechanism is completely differentiated from electrical devices and other molecular photo-switch-based approaches. Beyond vision restoration, it is a generally useful approach for controlling excitable cells. If successful, it may have a great impact on patients who are underserved by current treatments. The interdisciplinary research provides excellent educational opportunities for participating graduate and undergraduate students. The proposing team has an exceptional record on inclusion of women, under-represented minorities, and undergraduates in their research. They also have a good track record on outreach to the local community, and planned outreach activities include Research Experience for Teachers and activities for K-12 students.Technical Description Nanophotoswitch (NPS) offers a new tool to elicit electrical activity for basic science studies of neuronal function, both in vitro and also potentially in vivo. The hypothesis is based on the NPS design and results of pilot experiments, that light induces an electrical dipole in the NPS. Preliminary data indicate that an NPS based on ruthenium bipyridine (Rubpy) inserts into cell membranes and upon visible-wavelength illumination triggers action potentials in cultured excitable cells and in wholemount rat retina. When injected into the eye of blind photoceptor-degenerate rats, visual stimulation induces electrical activity in the superior colliculus. It was also demonstrated that NPS can both depolarize or hyperpolarize the membrane, depending on the environmental redox potential. This unique combination of bi-directional modulation of the membrane potential in one biophotonic switch affords the ability to both activate and inhibit the action potential firing of the illuminated cells with the same molecule, presenting largely increased flexibility in neuronal control. The NPS would be useful in studying any electrically excitable cell, including, for example, cardiomyocytes, smooth muscle cells, neuroendocrine cells, and certain glial and cancer cells. Since light-activated signaling unit is individual neurons, a visual prosthesis based on NPS system has the potential to provide higher visual acuity for the millions of patients with photoreceptor loss due to retinal degenerative diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Distinct from other nano-scale optical cellular modulating approaches using optogenetics or azobenzene-based photoswitches, this approach obviates the need for gene manipulation, toxic ultraviolet illumination or immunogenic molecules, due to the unique light-to-electrical signal transduction mechanism of the NPS.