The importance of protein kinase G (PKG) for cGMP-dependent cell death and neuroprotection in inherited retinal neurodegeneration

蛋白激酶 G (PKG) 对于遗传性视网膜神经变性中 cGMP 依赖性细胞死亡和神经保护的重要性

• 批准号: 212312876
• 负责人: Professor Dr. Francois Paquet-Durand
• 金额: --
• 依托单位: Forschungsinstitut für Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/212312876?language=en
• 关键词: importance; protein; kinase; PKG; cGMP

Retinitis Pigmentosa (RP) is a group of inherited retinal degenerations which constitutes one of the leading causes of blindness in the developed world. These are at present untreatable and the underlying neurodegenerative mechanisms are unknown even though the genetic causes are often established. Since elevated levels of cyclic guanosine monophosphate (cGMP) are responsible for photoreceptor cell death in different animal models for human RP, differential regulation of factors involved in cGMP signalling may represent a novel approach for the treatment of RP. The aim of this study is to investigate cGMP-signalling and its role in photoreceptor degeneration using in vivo, ex vivo, and in vitro techniques. The project will focus on the activity of cGMPdependent protein kinase G (PKG), its potential targets during retinal degeneration, and the identification of neuroprotective strategies to halt or delay processes leading to blindness. This will be accomplished by in vivo phenotyping of treated and untreated mice of the lines studied, and the follow-up of degenerative events in the same individual animals using state-of-the-art, non invasive technology for both functional and morphological characterization. At certain time points, a number of animals will be sacrificed for ex vivo studies with emphasis on assessing metabolic activity of calpains, poly-ADP-ribose-polymerase (PARP), and histone deacetylases (HDAC) as potential downstream effectors of cGMP-PKG. New data on processes active during retinal neurodegeneration will serve as basis for developing and testing novel experimental treatments on in vitro retinal explants, and where applicable, in vivo.

色素性视网膜炎（RP）是一组遗传性视网膜变性，其构成发达国家失明的主要原因之一。这些是目前无法治疗的，潜在的神经退行性机制是未知的，即使遗传原因往往是确定的。由于环磷酸鸟苷（cGMP）的水平升高是负责感光细胞死亡在不同的动物模型的人RP，差异调节的因素参与cGMP信号可能代表一种新的方法治疗RP。本研究的目的是研究cGMP信号转导及其在光感受器变性中的作用，使用体内，体外和体外技术。该项目将重点关注cGMP依赖性蛋白激酶G（PKG）的活性，其在视网膜变性过程中的潜在靶点，以及确定神经保护策略以阻止或延迟导致失明的过程。这将通过对研究品系的经处理和未经处理小鼠进行体内表型分析，以及使用最先进的非侵入性技术对相同个体动物的退行性事件进行随访以进行功能和形态学表征来实现。在某些时间点，将处死许多动物进行离体研究，重点是评估钙蛋白酶、聚ADP核糖聚合酶（PARP）和组蛋白脱乙酰酶（HDAC）作为cGMP-PKG的潜在下游效应物的代谢活性。视网膜神经变性过程中活跃的新数据将作为开发和测试体外视网膜外植体和体内（如适用）新实验治疗的基础。