Necroptosis, neuroprotection and axonal regeneration in retina ganglion cell injury

 描述(申请人提供)：青光眼影响全球7000万人[1，2]，以视神经萎缩和视网膜神经节细胞(RGC)进行性死亡为特征[3]。青光眼通常与眼压升高有关，目前的治疗目标是降低眼压[4]。然而，尽管降眼压治疗延缓了青光眼的发展和进展，但接受适当治疗的人中约有10%继续经历失明[2]。因此，研究RGC死亡的潜在机制可能会提高我们对疾病病理生理学的理解，并导致新的治疗方法。因此，迫切需要有效的神经保护，但不幸的是，目前还没有有效的治疗方法。尽管细胞凋亡已被证明是细胞死亡的一种主要形式，但仅基于抑制这一重要方式的干预未能达到预期的目标。我们最近证明，在视网膜脱离的视网膜变性模型中，除了caspase依赖的细胞凋亡外，RIP激酶介导的坏死(也称为坏死性下垂)也参与了光感受器的死亡，有效的神经保护需要联合治疗。我们建议在青光眼动物模型中研究RIP激酶途径与半胱氨酸天冬氨酸氨基转移酶的结合是否可以成为一种新的治疗靶点。我们希望将我们关于细胞死亡途径冗余的发现从我们在光感受器退化方面的工作扩展到青光眼的动物模型。我们建议评估RIPK和Caspase抑制(单独和联合)对视神经损伤后的神经保护和轴突再生的作用，并检测RIPK抑制和RIP3缺失对视神经挤压后RGC变性的自噬和炎性小体的影响。

 DESCRIPTION (provided by applicant): Glaucoma affects 70 million people worldwide [1, 2] and is characterized by optic nerve (ON) atrophy and the progressive death of retinal ganglion cell (RGC) [3]. Glaucoma is often associated with elevated intraocular pressure (IOP), and current management aims at lowering IOP [4]. Yet although IOP-lowering treatments slow the development and progression of glaucoma, approximately 10% of people who receive proper treatment continue to experience loss of vision [2]. Therefore, investigation of the underlying mechanisms involved in RGC death is likely to improve our understanding of the disease pathophysiology and lead to novel therapeutic approaches. Effective neuroprotection thus is urgently needed, but unfortunately there are no effective treatments available. Although apoptosis has been shown to be a major form of cell death, interventions based solely on inhibition of this important modality have failed to achieve the desired goal. We recently demonstrated that RIP kinase-mediated necrosis (also known as necroptosis) in addition to caspase-dependent apoptosis is involved in photoreceptor death in a retinal detachment model of retinal degeneration and that effective neuroprotection necessitates combination therapy. We propose to study whether the RIP kinase pathway in combination with caspases can be a novel therapeutic target in animal models of glaucoma. We would like to expand our findings on the redundancy of cell death pathways from our work in photoreceptor degenerations to animal models of glaucoma. We propose to evaluate the neuroprotective and axonal regenerative effects of RIPK and Caspase Inhibition (alone and in combination) after optic nerve injury and examine the effects of RIPK inhibition and RIP3 deletion on autophagy and inflammasomes in RGC degeneration after optic nerve crush.