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（由申请人提供）：神经细胞死亡发生在许多视网膜变性，包括AMD。尽管存在用于AMD的“湿”形式的部分疗法，但是对于“干”形式没有有效的疗法，其特征在于视网膜色素上皮细胞和光感受器的进行性损失。因此，迫切需要有效的神经保护，但不幸的是，目前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主要形式，但仅基于抑制这一重要形式的干预措施未能实现预期目标。我们最近证明，RIP激酶介导的坏死（也称为坏死性凋亡），除了半胱天冬酶依赖性细胞凋亡参与视网膜变性的视网膜脱离模型中的感光细胞死亡，有效的神经保护需要联合治疗。我们建议研究RIP激酶通路与半胱天冬酶结合是否可以成为其他视网膜变性动物模型（如AMD）的新治疗靶点。Yang等人（NEJM 2008）确定TLR 3多态性与AMD相关，并且PolyI：C（dsRNA类似物）介导的动物TLR 3激活导致萎缩性AMD样变化。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/小胶质细胞在动物模型中显著促进视网膜变性。我们已经看到，RIP 3-/-基因缺失减少了炎症浸润，但如果从所有细胞或免疫细胞中删除RIP 3-/-就足以起到神经保护作用，这一点仍然没有答案。我们建议通过评估RIPK和半胱天冬酶抑制（单独和组合）在Poly I：C AMD模型中的神经保护作用，将我们关于从视网膜脱离模型到AMD动物模型的细胞死亡途径冗余的发现扩展。除了进一步研究神经保护机制外，我们还将通过在WT和RIP 3之间进行骨髓移植（BMT）来研究免疫系统在视网膜毒性聚I：C模型中RIP 3-/-神经保护机制中的作用-/-小鼠。