Modeling and mechanistic investigation of a novel dry AMD mouse model with CLIC4 deleted in RPE

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SUMMARY Aged-related macular degeneration (AMD) is a complex disease and the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen deposits are the silent hallmark of dry AMD. The retinal pigment epithelium (RPE) is likely to be the primary lesion site of AMD. Lacking an AMD mouse model is a roadblock to advance this research field. Recently we showed that RPE-specific CLIC4 knockout (KO) mice develop a full spectrum of AMD-like pathophysiology, including the impaired visual function, the drusen-like deposition, and severe RPE cell loss. CLIC4 is a redox-sensing pleiotropic protein. Our characterizations showed CLIC4 deficiency alters a myriad of signaling pathways that are required for maintaining RPE homeostasis. In particular, CLIC4-KO RPE cells had profound lipid dysregulation. We proposed two specific aims to understand CLIC4's role in coupling several aspects of the lipid homeostasis-metabolism, storage, and transport. We will investigate the lipid homeostasis of the RPE in the context of cell biology. The overarching goal is to learn how integrated outcomes as a consequence of loss-of-CLIC4 present the AMD-like pathophysiology. We will investigate CLIC4’s role in the phospholipid (Aim1) and sphingolipid (Aim2) homeostasis of RPE (Aim1) in the aspects of the lipid metabolism, storage, and transport. We will use interdisciplinary approaches and state-of-the-art techniques (e.g., Imaging Mass Spectrometry- LC/MS-MS lipidomics, transcriptomes, 3D electron microscopy) to studies these questions both in vivo and in vitro. The obtained information will significantly advance our comprehension of the basic science of the RPE and AMD etiology. They also have a strong potential for discovering new drug targets to treat AMD.