Necroptosis, neuroprotection and axonal regeneration in retina ganglion cell injury

视网膜神经节细胞损伤中的坏死性凋亡、神经保护和轴突再生

基本信息

批准号：
9042374
负责人：
Demetrios Vavvas
金额：
$ 36.9万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042374
关键词：
Achievement Affect Animal Disease Models Animal Model Apoptosis Atrophic Autophagocytosis Benchmarking Blindness CASP1 gene Caspase Caspase Inhibitor Cell Death Cell Survival Cells Cessation of life Combined Modality Therapy Crush Injury Cytoprotection Data Development Disease Dose Evaluation Functional disorder Glaucoma Goals Health IL18 gene Individual Intervention Investigation Knock-out LAMP-2 Lead Literature Mediating Modality Modeling Mus Natural regeneration Necrosis Nerve Crush Neurons Optic Nerve Optic Nerve Injuries Pathway interactions Patients Phosphotransferases Photoreceptors Physiologic Intraocular Pressure RIPK3 gene Retina Retinal Degeneration Retinal Detachment Retinal Ganglion Cells Role Time TimeLine Visual Work axon growth axon regeneration base cell injury effective therapy experience ganglion cell improved inhibition of autophagy inhibitor/antagonist interleukin-1beta-converting enzyme inhibitor neuroprotection new therapeutic target novel novel therapeutic intervention novel therapeutics optic nerve disorder photoreceptor degeneration regenerative response

项目摘要

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.

描述（由适用提供）：青光眼影响了全球7000万人[1，2]，其特征是视神经（ON）萎缩和视网膜神经节细胞（RGC）的进行性死亡[3]。青光眼通常与眼内压（IOP）升高有关，目前的管理旨在降低IOP [4]。然而，尽管降低IOP的治疗降低了青光眼的发展和发展，但大约有10％的接受适当治疗的人继续经历视力丧失[2]。因此，对RGC死亡涉及的潜在机制的研究可能会改善我们对疾病病理生理学的理解，并导致新型的治疗方法。因此，迫切需要有效的神经保护作用，但不幸的是没有有效的治疗方法。尽管凋亡已被证明是细胞死亡的一种主要形式，但仅基于抑制这种重要方式的干预措施未能实现所需的目标。我们最近证明，除caspase依赖性凋亡外，RIP激酶介导的坏死（也称为坏死）在视网膜变性和有效的神经保护性必要的组合治疗中与光感受器死亡有关。我们建议研究与胱天蛋白酶结合使用的RIP激酶途径是否可以成为青光眼动物模型中的新型治疗靶标。我们想扩大有关细胞死亡途径的冗余的发现，从我们在光感受器退化的工作到青光眼动物模型。我们建议评估视神经损伤后RIPK和CASPase抑制（单独和组合）的神经保护性和轴突再生作用，并检查了光神经压碎后RGC变性中RGC变性的RIPK抑制和RIP3缺失对自噬和炎症的影响。