Calcium channels in retinal photoreceptors

视网膜感光细胞中的钙通道

• 批准号: 10375922
• 负责人: AMY LEE
• 金额: $ 47.65万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375922
• 关键词: Affect; Animal Model; Architecture; Binding; Blindness; C-terminal; Calcium Channel; Calmodulin; Cell Adhesion Molecules; Cell Transplantation; Clinical; Communication; Cone; Data; Development; Disease; Electrophysiology (science); Financial compensation; Genes; Glutamates; Goals; Human; Image; In Vitro; Injury; Ions; Knock-in Mouse; Knowledge; Lead; Lighting; Mediating; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Neurites; Neurophysiology - biologic function; Night Blindness; Pathologic; Pathway interactions; Photoreceptors; Point Mutation; Positioning Attribute; Process; Property; Proteins; RNA Splicing; Recombinants; Research; Resistance; Retina; Retinal Cone; Retinal Diseases; Retinal Photoreceptors; Rod; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; Source; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Transfection; Triad Acrylic Resin; Variant; Vertebrate Photoreceptors; Vision; Visual impairment; Work; biophysical properties; in vivo; inducible gene expression; innovation; insight; molecular assembly/self assembly; mutant; novel strategies; postsynaptic; presynaptic; retinal rods; ribbon synapse; scaffold; sensor; sight restoration; synaptogenesis; transmission process; transplantation therapy; voltage

The long-term goal of our research is to understand how the properties of Cav channels shape their neural functions. The objective of this competing renewal application is to define the Cav1-dependent signaling pathways that shape the development and plasticity of the photoreceptor (PR) synapse. Among the major Cav1 subtypes expressed in the retina, Cav1.4 is uniquely critical for PR synaptogenesis. How Cav1.4 contributes to this process remains a mystery—a major challenge being that available animal models do not distinguish between the roles of Cav1.4 as a source of Ca2+ ions and as a scaffold for synaptogenic proteins. To overcome this hurdle, we generated a knock-in mouse strain expressing a non-conducting mutant form of Cav1.4. While the molecular organization of PR synapses is largely spared in these mice, the maturation of synaptic ribbons and invagination of postsynaptic neurites into PR terminals is disrupted. Our findings raise the intriguing possibility that the clinical variability associated with CSNB2 could arise from heterogeneous impacts of the mutations on the organization, development, and mature function of the PR synapse. Our central hypothesis is that Cav1.4 mediates Ca2+ signaling pathways that promote the maturation of synaptic ribbons and the postsynaptic architecture of PR synapses via mechanisms that are disrupted in CSNB2. We will test this hypothesis with the following Aims: (1) Elucidate the mechanism whereby Cav1.4 Ca2+ signals regulate the maturation and plasticity of synaptic ribbons (2) Define the role of Cav1 Ca2+ signals in enabling the postsynaptic wiring of PR synapses (3) Determine the impact of pathological variants of human Cav1.4 channels on PR synapse structure and function. The overall impact of our research will be knowledge of: (a) the multi-faceted roles of Cav channels at a synapse that is crucial for vision, and (b) how dysregulation specifically of Cav1.4 could lead to heterogeneous forms of vision impairment. More broadly, our research is expected to provide insights into mechanisms that enable the proper synaptic connectivity in the retina—a requirement for the successful restoration of vision through cell transplantation therapies.

我们研究的长期目标是了解Cav通道的特性如何塑造它们的形状。 神经功能此竞争性续签申请的目的是定义Cave 1依赖者 形成感光器（PR）突触的发育和可塑性的信号通路。之间 Cav1.4是视网膜中表达的主要Cav 1亚型，对于PR突触发生具有独特的关键作用。如何 Cav1.4对这一过程的贡献仍然是一个谜-一个主要的挑战是，可用的动物 模型没有区分Cav1.4作为Ca 2+离子来源和作为支架的作用， 突触形成蛋白为了克服这一障碍，我们产生了表达Cav1.4的非传导突变形式的敲入小鼠品系。虽然PR突触的分子组织在很大程度上幸免于难， 这些小鼠，突触带的成熟和突触后神经突内陷到PR终末 被打乱了我们的研究结果提出了一种有趣的可能性，即与CSNB 2相关的临床变异性 可能源于突变对组织、发展和成熟的异质性影响。 PR突触的功能。我们的中心假设是Cav1.4介导Ca 2+信号通路， 促进突触带的成熟和PR突触的突触后结构， 在CSNB 2中被破坏的机制。我们将测试这个假设与以下目的：（1）阐明 Cav1.4 Ca ~（2+）信号调节突触带成熟和可塑性的机制（2）定义 Cav 1 Ca 2+信号在PR突触的突触后布线中的作用（3）确定 人类Cav1.4通道的病理变异对PR突触结构和功能的影响。我们的整体影响 研究将是以下知识：（a）Cav通道在对视觉至关重要的突触处的多方面作用， 以及（B）Cave 1.4的调节异常如何导致不同形式的视力障碍。更 广泛地说，我们的研究有望提供对机制的见解，使适当的突触 视网膜的连通性-通过细胞移植成功恢复视力的必要条件 治疗