Necroptosis and Neuroprotection in AMD

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。尽管针对“湿”型AMD存在部分治疗方法，但对于以视网膜色素上皮细胞和光感受器逐渐丧失为特征的“干”型AMD尚无有效治疗方法。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。虽然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方式的干预措施未能达到预期的目标。我们最近证明，RIP激酶介导的坏死（也称为坏死性上睑塌陷）和caspase依赖性细胞凋亡参与视网膜退变视网膜脱离模型中的光受体死亡，有效的神经保护需要联合治疗。我们建议研究RIP激酶途径联合caspases是否可以成为其他视网膜变性动物模型（如AMD）的新的治疗靶点。Yang等（NEJM 2008）发现TLR3多态性与AMD相关，PolyI:C （dsRNA的类似物）介导的TLR3激活在动物中导致萎缩性AMD样变化。此外，我们和其他实验室的几项研究表明，骨髓（BM）来源的巨噬细胞/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，RIP3-/-基因缺失减少了炎症浸润，但是否从所有细胞或免疫细胞中删除RIP3-/-足以起到神经保护作用仍然没有答案。我们建议通过评估RIPK和Caspase抑制（单独和联合）在Poly I:C AMD模型中的神经保护作用，将我们关于细胞死亡途径从视网膜脱离模型到AMD动物模型的冗余研究结果扩展到AMD动物模型。为了进一步研究RIP3-/-的神经保护机制，我们将通过对WT和RIP3-/-小鼠进行骨髓移植（Bone Marrow Transplant， BMT），研究免疫系统在RIP3-/-神经保护机制中的作用。

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.