Necroptosis and Neuroprotection in AMD

AMD 中的坏死性凋亡和神经保护

• 批准号: 8512015
• 负责人: Demetrios Vavvas
• 金额: $ 20.35万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512015
• 关键词: Achievement; Affect; Animal Disease Models; Animal Model; Animals; Apoptosis; Benchmarking; Bone Marrow; Bone Marrow Transplantation; Caspase; Caspase Inhibitor; Cell Death; Cells; Cessation of life; Combined Modality Therapy; Cytoprotection; Data; Development; Disease; Disease model; Dose; Double-Stranded RNA; Evaluation; Exudative age-related macular degeneration; Genetic; Genetic Polymorphism; Goals; Immune; Immune system; Infiltration; Inflammatory Infiltrate; Intervention; Knock-out; Laboratories; Lead; Leucocytic infiltrate; Mediating; Microglia; Modality; Modeling; Mus; Necrosis; Neurons; Nonexudative age-related macular degeneration; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Photoreceptors; Poly I-C; RIPK3 gene; Retinal; Retinal Degeneration; Retinal Detachment; Retinal Diseases; Role; Structure of retinal pigment epithelium; TLR3 gene; Time; TimeLine; Toxic effect; Visual; Work; Yang; analog; base; effective therapy; inhibitor/antagonist; macrophage; neuroprotection; new therapeutic target; novel; public health relevance; response

DESCRIPTION (provided by applicant): Neural cell death occurs in many retinal degenerations including AMD. Although partial therapies exist for the "wet" form of AMD there is no effective therapy for the "dry" form, which is characterized by progressive loss of retinal pigment epithelial cells and photoreceptors. Thus, effective neuroprotection is urgently needed but unfortunately there are no effective treatments currently 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 other animal models of retinal degeneration such as AMD. Yang et al (NEJM 2008) identified TLR3 polymorphism to be associated with AMD and that PolyI:C (analog of dsRNA) mediated activation of TLR 3 in animals leads to atrophic AMD like changes. Additionally, several studies from us and other laboratories have shown that bone-marrow (BM) derived macrophages/microglia significantly contribute to retinal degeneration in animal models. We have seen that RIP3-/- genetic deletion decreases inflammatory infiltrate but it remains unanswered if RIP3-/- deletion from all cells or from immune cells can suffice for neuroprotection. We propose to expand our findings on the redundancy of cell death pathways from the retinal detachment model to animal models of AMD by evaluating the neuroprotective effects of RIPK and Caspase Inhibition (alone and in combination) in the Poly I:C model of AMD. In addition to further examine the mechanism of neuroprotection we will study the role of immune system in the mechanism of RIP3-/- neuroprotection in the poly I:C model of retinal toxicity by performing Bone Marrow Transplant (BMT) between WT and RIP3-/- mice.

描述（申请人提供）：神经细胞死亡发生在包括AMD在内的许多视网膜变性中。尽管对于AMD的“湿”形式存在部分疗法，但对于“干”形式没有有效的治疗方法，其特征是视网膜色素上皮细胞和感光体的进行性丧失。因此，迫切需要有效的神经保护作用，但不幸的是目前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）在视网膜变性的视网膜脱离模型中与光感受器死亡有关，并且有效的神经保护需要组合治疗。我们建议研究在其他视网膜变性动物模型（如AMD）中，RIP激酶途径与胱天蛋白酶结合使用是否可以成为一种新型的治疗靶标。 Yang等人（NEJM 2008）确定TLR3多态性与AMD相关，而Polyi：C（DSRNA的类似物）介导的动物中TLR 3的激活导致萎缩AMD，如变化。此外，我们和其他实验室的几项研究表明，骨髓（BM）衍生的巨噬细胞/小胶质细胞显着有助于动物模型的视网膜变性。我们已经看到，RIP3 - / - 遗传缺失会降低炎症性浸润，但如果所有细胞中的RIP3 - / - 缺失或免疫细胞的RIP3 - / - 缺失仍然足以进行神经保护。我们建议通过评估RIPK和caspase抑制的神经保护作用（单独和组合）在Poly I：C AMD的AMD模型中，通过评估RIPK和CASPase抑制的神经保护作用，将细胞死亡途径冗余的发现从视网膜脱离模型扩展到AMD的动物模型。除了进一步检查神经保护的机制外，我们还将研究免疫系统在RIP3 - / - 神经保护机理中的作用，通过在WT和RIP3 - / - 小鼠之间进行骨髓移植（BMT），通过进行骨髓移植（BMT），通过进行视网膜毒性的Poly I：C模型。