Retinal Nanophotoswitch

建议：1404089 PI：Humayun，Mark S.视网膜纳米光开关的意义所提出的研究的目的是开发一种新的神经光子分子开关的光激活的神经元。基于这种纳米光开关（nanopotoswitch，缩写为nanopotoswitch）的视觉假体有可能改善数百万患有视网膜退行性疾病（如视网膜色素变性和年龄相关性黄斑变性）的患者的视力。这一建议非常具有创新性。生物物理机制与电子设备和其他基于分子光开关的方法完全不同。除了视力恢复之外，它还是控制易兴奋细胞的一种普遍有用的方法。如果成功，它可能会对目前治疗不足的患者产生巨大影响。跨学科研究为参与研究生和本科生提供了极好的教育机会。提议团队在将女性，代表性不足的少数民族和本科生纳入其研究方面有着特殊的记录。此外，他们在与当地社区的联系方面也有着良好的记录，计划中的联系活动包括教师研究体验和K-12学生活动。技术说明纳米光电开关（Nanophotoswitch，简称NPSB）为神经元功能的基础科学研究提供了一种新的工具，可以在体外和体内激发电活动。该假设是基于光的设计和试点实验的结果，即光诱导的电偶极子中的光。初步数据表明，钌联吡啶（Rubpy）的基础上插入细胞膜和可见光波长照明触发动作电位在培养的可兴奋细胞和在wholemount大鼠视网膜。当注射到失明的光感受器退化大鼠的眼中时，视觉刺激诱导上级丘的电活动。研究还表明，依环境氧化还原电位的不同，氧化还原酶既可使膜脱钙，也可使膜增钙。在一个生物光子开关中膜电位的双向调节的这种独特组合提供了用相同分子激活和抑制被照射细胞的动作电位放电的能力，在神经元控制中表现出大大增加的灵活性。该仪器可用于研究任何电兴奋细胞，包括心肌细胞、平滑肌细胞、神经内分泌细胞和某些神经胶质细胞和癌细胞。由于光激活的信号单元是单个神经元，基于光激活系统的视觉假体具有为数百万因视网膜变性疾病（如视网膜色素变性（RP）和年龄相关性黄斑变性（AMD））而导致的感光细胞丧失的患者提供更高视力的潜力。与其他使用光遗传学或基于偶氮苯的光开关的纳米级光学细胞调节方法不同，由于微生物体独特的光电信号转导机制，这种方法避免了对基因操作、有毒紫外线照射或免疫原性分子的需要。

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.