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

视网膜色素变性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。这些疾病目前是无法治愈的，潜在的神经退化机制尚不清楚，尽管遗传原因往往是确定的。由于在不同的人RP动物模型中，cGMP水平升高是导致光感受器细胞死亡的原因，对cGMP信号转导相关因子的差异调节可能是治疗RP的一种新途径。这项研究的目的是利用体内、体外和体外技术研究cGMP信号及其在光感受器退化中的作用。该项目将专注于cGMP依赖的蛋白激酶G(PKG)的活性，它在视网膜变性过程中的潜在靶点，以及确定阻止或延迟导致失明的过程的神经保护策略。这将通过对研究品系中处理过的和未处理过的小鼠进行体内表型鉴定，并使用最先进的、非侵入性的功能和形态表征技术对同一个体动物的退化事件进行跟踪来实现。在某些时间点，一些动物将被处死进行体外研究，重点评估钙蛋白酶、多聚ADP核糖聚合酶(PARP)和组蛋白脱乙酰酶(HDAC)作为cGMP-PKG潜在下游效应因子的代谢活性。有关视网膜神经变性过程中活跃过程的新数据将成为开发和测试体外视网膜外植体的新实验治疗方法的基础，如果适用，还将在体内进行。

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.