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

基本信息

批准号：
10915597
负责人：
Ching-Kang Jason Chen
金额：
$ 34.51万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/10915597
关键词：
Ablation Adult Amacrine Cells Animals Automobile Driving Birth Cell Density Cells Chemical Synapse Collaborations Color blindness Cone Couples DNQX Darkness Defect Development Diltiazem Electrical Synapse Etiology Future GTP-Binding Proteins Genetic Human Image Knockout Mice Knowledge Light Light Cell Mediating Metabotropic Glutamate Receptors Methodology Modality Morphology Mus Mutation Names Pathway interactions Patients Periodicity Photophobia Photoreceptors Phototransduction Physiological Retina Retinal Cone Retinal Ganglion Cells Retinal Pigments Rod Role Signal Transduction Signaling Molecule Structure Synapses Testing Therapeutic Transducin Vertebrate Photoreceptors Vision Work achromatopsia alpha Subunit Transducin channel blockers clinically relevant combat dark rearing human disease inhibitor innovation light effects melanopsin neuron development novel outer plexiform layer patch clamp pharmacologic postnatal postnatal development presynaptic response retinal neuron retinal rods sildenafil starburst amacrine cell success synaptogenesis

项目摘要

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.

在所谓的 KK 小鼠中，视杆细胞和视锥细胞转导蛋白 α 亚基的基因消融并没有像我们所研究的那样使外视网膜沉默。研究人员发现，视网膜内部神经元仍然对光有强烈的反应，这种与转导蛋白无关的光令人惊讶。敏感性并不依赖于本质上感光的视网膜神经节细胞中的黑视蛋白信号传导。 3K 小鼠中体现的“不依赖转导蛋白和黑视蛋白的光转导（TMIP）”显然有效我们已经证明，TMIP 可以通过视网膜中一种未知且可能新颖的信号机制产生光。信号通过视网膜回路，能够驱动视网膜神经节细胞，赋予成像视觉。 TMIP 发生在发育和成熟的视杆细胞和/或视锥细胞光感受器中，由视色素介导和三聚体 G 蛋白，对于出生后正常视网膜发育必不可少。在 Aim-1 中，我们将研究细胞。 TMIP 的起源，以确定杆和/或锥体作为 TMIP 发生的候选地点的相对贡献。 Aim-2 我们将测试 TMIP 中已知视觉色素的参与情况，以及三聚体 G 蛋白和其他候选物 Aim-3 旨在全面表征 TMIP 在光依赖性产后视网膜中的作用。当转导蛋白依赖的传统光转导尚未出现时，该应用正在发展。包含新颖的发现、概念、材料和方法的创新，意义在于进步。光转导和视网膜发育领域，与解释有关奥秘的临床相关性涉及 Gnat2 和 Cnga3 突变的不完全人类全色盲。