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

色素性视网膜炎（RP）是一组遗传性视网膜变性，是发达国家致盲的主要原因之一。这些目前是无法治疗的，即使遗传原因经常被确定，潜在的神经退行性机制也是未知的。由于环鸟苷单磷酸（cGMP）水平升高在不同的人类RP动物模型中负责光感受器细胞死亡，因此cGMP信号传导相关因子的差异调节可能代表了RP治疗的新方法。本研究的目的是利用体内、离体和体外技术研究cgmp信号传导及其在光感受器变性中的作用。该项目将重点关注cmpp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。这将通过对研究系的治疗和未治疗小鼠进行体内表型分析，并使用最先进的非侵入性技术对同一只动物的退化事件进行功能和形态表征来完成。在特定的时间点，一些动物将被处死进行体外研究，重点是评估钙蛋白酶、聚adp核糖聚合酶（PARP）和组蛋白去乙酰化酶（HDAC）作为cGMP-PKG的潜在下游效应物的代谢活性。在视网膜神经退行性变过程中活跃的新数据将作为开发和测试体外视网膜移植的新实验治疗的基础，并在适用的情况下在体内进行。

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.