Sunday, May 11, 2025
5/11/2025
Deciphering the role of mitochondrial/autophagy dysfunction in regulating inflammatory processes during AMD pathogenesis - Project Summary: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly and is driven by multiple genetic and environmental factors that lead to severe loss of central vision. However, no definitive treatment options are available for the dry form of the disease. Inflammation has been known to play an important role in maintaining tissue homeostasis. However, a deregulated inflammatory response is associated with tissue damage and the onset of several aging diseases, including AMD. Even though several studies have demonstrated the role of inflammation in AMD pathogenesis, the underlying mechanism controlling the inflammatory cascades, particularly driving the onset of chronic inflammation in AMD, still remains unknown. We have recently reported the novel finding that in dry AMD patients9,10 and in a mouse model of dry AMD, there is inflammation induction due to the activation of Akt2 signaling in the retinal pigment epithelial (RPE) cells-the first cells affected in dry AMD. Importantly, Akt2 inhibition in this mouse model reduced retinal inflammation and alleviated early RPE changes. Additionally, AMD patients also have increased Akt2 levels in the macular RPE cells relative to controls. Therefore, to evaluate the role of Akt2 activation in RPE health and in retinal degeneration, we have generated RPE-specific Best1 (Akt2) constitutive knock-in (KI) mice. These mice show a dry AMD-like phenotype, as evident from basal laminar deposits, decreased ezrin expression, hyperpigmentation, and morphological alterations in the RPE, as well as decreased retinal function. We propose to use this mouse model and iPSC-derived RPE from CFH(Y/Y) [controls] and CFH(H/H) [AMD risk allele containing] donors as novel tools in this study for testing our central hypothesis that “activation of Akt2 signaling in the RPE triggers mitochondrial/autophagy dysfunction leading to oxidative stress and inflammation, which are critical factors in early AMD pathogenesis”. To address this hypothesis, we propose the following aims: Specific Aim 1 (mentored phase): To test our hypothesis that Akt2 overexpression in the RPE elicits mitochondrial/mitophagy dysfunction thereby inducing oxidative stress; Specific Aim 2 (mentored phase): To test our hypothesis that activation of Akt2 in the RPE drives retinal inflammation; Specific Aim 3 (independent phase): To test our hypothesis that the molecular cascades associated with autophagy-mediated regulation of inflammation are critical in AMD pathogenesis. The proposed study is significant because we will use a unique, state-of-the-art in vivo animal model and extend our studies to human iPSC-derived RPE samples to investigate how inflammation contributes to vision loss in AMD and develop strategies potentially leading to a new treatment modality for early, dry AMD.
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