Unraveling the Activation Mechanism and Therapeutic Potential of PEDF-R

Retinal degeneration (RD) is a debilitating group of disorders that significantly impair vision and quality of life. By 2040, it is estimated that nearly 300 million people worldwide will experience vision loss due to RD. Despite the growing burden of this condition, current treatment options remain limited and largely ineffective at halting disease progression. Pigment epithelium-derived factor (PEDF) is a neuroprotective glycoprotein known to support retinal health by interacting with its receptor, PEDF-R, which is expressed on the surface of retinal pigment epithelial (RPE) cells. PEDF-R activation induces phospholipase activity that contributes to cellular homeostasis and survival. As a result, PEDF-R represents a promising but underexplored therapeutic target for RD. To date, therapeutic development has focused primarily on PEDF-derived peptide drugs. However, peptides often suffer from poor stability, limited bioavailability, and delivery challenges. Our long-term goal is to develop small-molecule drugs targeting PEDF-R that overcome these limitations and have strong potential for clinical translation. This application is driven by two complementary objectives. Aim I is to elucidate the structural mechanisms underlying PEDFPEDF-R signaling using ingle-particle cryo-electron microscopy (cryo-EM). Interestingly, the same protein encoded by the PNPLA2 gene also ocalizes to intracellular lipid droplets, where it functions as adipose triglyceride lipase (ATGL). Activated by ABHD5, TGL catalyzes the hydrolysis of triglycerides and exhibits enzymatic promiscuity, releasing both sn-1 and sn-2 fatty cids. In contrast, PEDF-R at the plasma membrane selectively releases sn-2 fatty acids. These distinct activities uggest PEDF-R may adopt different conformations depending on cellular localization and folding state. Structural etermination of both forms will lay the groundwork for rational structure-based drug design. Aim II addresses the urrent lack of tools for functional screening of PEDF-R-targeted compounds. Docosahexaenoic acid (DHA), a key ipid involved in retinal development and health, has been identified as a major product of PEDF-R activity and orrelates with its functional output. We hypothesize that DHA can serve as a real-time biochemical reporter of PEDFR’s phospholipase activity. Recent advances in biosensor technology have demonstrated the utility of inserting ircularly permuted green fluorescent proteins (cpGFPs) into G-protein-coupled receptors (GPCRs) to monitor etabolic signals. We will apply this protein design strategy to engineer DHA-sensitive GPCR biosensors. These iosensors will be employed in small-molecule screening assays using established compound libraries to identify andidate drugs that modulate PEDF-R activity. Together, this project will provide a detailed molecular understanding f PEDF-R function and enable the development of novel small-molecule therapeutics for retinal degeneration. Project Number: 5P20GM144230-05 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Shian Liu | Institution: WEST VIRGINIA UNIVERSITY, MORGANTOWN, WV | Award Amount: $243,048 | Activity Code: P20 | Study Section: ZGM1-RCB-W(C1) View on NIH RePORTER: https://reporter.nih.gov/project-details/11518609