Transducin and melanopsin independent phototransduction in postnatal retinal development

产后视网膜发育中转导蛋白和黑视蛋白独立的光转导

• 批准号: 10863477
• 负责人: Ching-Kang Jason Chen
• 金额: $ 26.07万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10863477
• 关键词: Transducin; melanopsin; independent; phototransduction; postnatal

Genetic ablations of rod and cone transducin alpha subunits in the so-called KK mice do not silent the outer retina as we have found that inner retinal neurons still robustly respond to light. This surprised transducin-independent light sensitivity does not depend on melanopsin signaling in intrinsically photosensitive retinal ganglion cells. This so-named “transducin- and melanopsin-independent phototransduction (TMIP)” embodied in the 3K mice apparently works through an unknown and potentially novel signaling mechanism in retina. We have shown that TMIP-generated light signal passes through retinal circuit and is capable of driving retinal ganglion cells to confer image-forming vision. We hypothesize that TMIP occurs in developing and mature rod and/or cone photoreceptors, mediated by visual pigment and trimeric G-proteins, and indispensable for normal postnatal retinal development. In Aim-1 we will study the cellular origin of TMIP to determining relative contributions of rod and/or cone as candidate venue where TMIP takes place. In Aim-2 we will test the involvement of known visual pigments in TMIP, as well as trimeric G-proteins and other candidate signaling molecules/pathways. Aim-3 is to fully characterize TMIP’s role in light-dependent postnatal retinal development at times when transducin-dependent conventional phototransduction is yet to emerge. This application contains novel findings, conceptual, material and methodological innovations. Significance lies in the advancement of the phototransduction and retinal development fields, with clinical relevance in explaining mysteries concerning incomplete human achromatopsia involving Gnat2 and Cnga3 mutations.

所谓的KK小鼠中的杆和锥体跨多霉素α亚基的遗传消融不会在我们的外部视网膜上保持沉默 发现内部仍然对光线有强烈的反应。这种令人惊讶的独立的透明蛋白的光 灵敏度不取决于内在光敏性视网膜神经节细胞中的黑色素蛋白信号传导。这是所谓的 3K小鼠体现在3K小鼠中的“透明蛋白和黑色素无关的光转导（TMIP）”显然起作用 通过视网膜中未知且潜在的新型信号传导机制。我们已经证明了TMIP生成的光 信号通过视网膜电路，能够驱动视网膜神经节细胞赋予图像形成视觉。我们 假设TMIP发生在发育和成熟的杆和/或锥形光感受器中，由视觉色素介导 和三聚体G蛋白，对于正常的产后残留发育而言是必不可少的。在AIM-1中，我们将研究细胞 TMIP的起源是确定杆和/或锥作为TMIP发生的候选场所的相对贡献。在 AIM-2我们将测试已知的视觉色素在TMIP中的参与，以及三聚体G蛋白和其他候选者 信号分子/途径。 AIM-3是充分表征TMIP在光依赖性后残留中的作用 有时尚未出现依赖性传统光转传的发育。此应用程序 包含新颖的发现，概念，物质和方法论创新。意义在于进步 光转导和残留开发领域，在解释有关的神秘性方面具有临床意义 涉及GNAT2和CNGA3突变的不完整的人achromoptia。