G-proteins and mechanisms of signal transduction in vision

G蛋白和视觉信号转导机制

• 批准号: 7945288
• 负责人: OLEG G KISSELEV
• 金额: $ 18.35万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7945288
• 关键词: Biochemical; Biological Models; Communities; Complex; Cyclic GMP; Data; Development; Drug Design; Electron Microscopy; Enzymes; Eye diseases; Future; G-protein Beta gamma; GTP-Binding Proteins; Goals; Grant; Heterotrimeric GTP-Binding Proteins; Human; In Vitro; Knock-out; Lead; Light; Light Adaptations; Mediating; Modeling; Morphology; Nucleotides; Pattern; Phenotype; Photoreceptors; Phototransduction; Physiology; Process; Property; Protein translocation; Proteins; Research; Resources; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Rhodopsin; Role; Second Messenger Systems; Signal Transduction; Staging; Synaptic Transmission; Testing; Therapeutic Intervention; Thick; Transducin; Vertebrate Photoreceptors; Vision; Vision research; Visual; Western Blotting; age effect; alpha Subunit Transducin; beta Subunit Transducin; in vivo; mouse model; novel; novel therapeutics; phosphoric diester hydrolase; protein complex; protein distribution; protein expression; research study; retinal rods; tool

DESCRIPTION (provided by applicant): Phototransduction in retinal rod photoreceptor cells relies on the prototypical mechanism of high-yield signal amplification mediated by the heterotrimeric G-protein transducin. A single light activated rhodopsin molecule activates several hundred transducin molecules, which relay the information about incoming visual signal from rhodopsin to the enzyme of the second messenger system, cGMP-phosphodiesterase. All aspects of transducin alpha subunit functions, especially its primary interactions with rhodopsin and rhodopsin catalyzed nucleotide exchange, require the transducin beta-gamma subunit complex. Discovered more than two decades ago, transducin beta-gamma has been studied by in-vitro experiments almost exclusively. The true in-vivo role of this protein complex during normal functioning or its involvement in retina diseases remains unknown. We have developed a novel tool to study the mechanisms of G-proteins in vision - a mouse model lacking the rod specific transducin gamma subunit. To characterize this model system, which we will make available to the broad vision research community, we propose to test major aspects of phototransduction, retina development and protein distribution. The key goal is to determine whether activation of visual signaling is possible at all without transducin beta-gamma complex, a problem that is not resolved by current in-vitro studies. In the future this model will also help to answer such important questions, as mechanisms of light adaptation, differences between rod and cone signaling, synaptic transmission, retina degeneration and others. G-protein beta-gamma complexes have recently emerged as new targets of drug design and therapeutic intervention. Thus, the functional characterization of this mouse model will be very valuable for understanding eye disease and potential new therapies in humans. PUBLIC HEALTH RELEVANCE: This project focuses on the first characterization of the mouse model system in which a key retinal protein, transducin beta-gamma complex, has been deleted. This model is being developed for use by the vision research community to help understand underlying mechanisms of retinal diseases in humans and facilitate novel therapeutic strategies.

描述（由申请人提供）：视网膜杆光感受器细胞中的光转导依赖于由异三聚体G蛋白透射蛋白介导的高收益信号扩增的原型机制。单个光激活的视紫红质分子激活了数百个跨丁蛋白分子，该分子将有关传入的视觉信号从视紫红质素传递到第二质体系CGMP-磷酸二酯酶的酶的信息。跨多霉素亚基功能的所有方面，尤其是其与视紫红质和视紫红质催化核苷酸交换的主要相互作用，都需要跨丁蛋白β-gamma亚基复合物。在二十多年前发现的，几乎完全通过体外实验研究了trandducin beta-gamma。该蛋白质复合物在正常功能或其参与视网膜疾病期间的真实体内作用仍然未知。我们已经开发了一种新的工具来研究视觉中G蛋白的机制 - 一种缺乏杆特异性透明胶γ亚基的小鼠模型。为了表征该模型系统，我们将向广泛的视力研究社区提供，我们建议测试光转导，视网膜开发和蛋白质分布的主要方面。关键目的是确定如果没有跨多霉素β-gamma复合物，是否可以激活视觉信号的激活，这一问题无法通过当前的体外研究解决。将来，该模型还将有助于回答此类重要问题，例如光适应机制，杆和锥信号之间的差异，突触传播，视网膜变性等。 G蛋白β-γ络合物最近成为药物设计和治疗干预的新靶标。因此，该小鼠模型的功能表征对于了解人类的眼病和潜在的新疗法非常有价值。 公共卫生相关性：该项目着重于小鼠模型系统的第一个表征，其中关键的视网膜蛋白质跨丁蛋白β-γ络合物已被删除。该模型正在开发供视觉研究界使用，以帮助了解人类视网膜疾病的基本机制，并促进新颖的治疗策略。