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.
Dry AMD affects millions of people in the USA and there is no effective treatment. Loss and cell death of photoreceptors is the major cause of the visual decline seen in this disease. Our work has uncovered novel redundant parallel cell death pathways in animal models of this disease and is identifying molecules to successfully interfere with them. These findings may lead to development of new drugs that can be used to help patients with dry AMD.
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|Hu, Yijun; Lin, Haijiang; Dib, Bernard et al. (2014) Cholesterol crystals induce inflammatory cytokines expression in a human retinal pigment epithelium cell line by activating the NF-ÎºB pathway. Discov Med 18:7-14|
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