Elucidating the GPCR protein networks that drive lymphatic growth

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Project Summary/ Abstract: Lymphatic diseases are numerous and affects upwards of 200 million people worldwide. These chronic disorders have limited clinical management and are broadly characterized by aberrant lymphatic vessel development and/or dysfunction which results in painful accumulation of interstitial fluid. Shockingly, no FDA-approved pharmacological treatments targeting lymphangiogenesis, the process of lymphatic vessel formation, are available. Thus, there is an urgent need to characterize key therapeutically tractable proteins and signaling pathways that regulate lymphangiogenesis. The Caron laboratory studies one such molecule, the potent pro-lymphangiogenic peptide, adrenomedullin (AM). AM-induced lymphangiogenesis requires formation of well-controlled AM-chemotactic gradients to provide directionality to growing and migrating lymphatic vessel tips. The atypical chemokine receptor 3 (ACKR3) is critical for the establishment of these gradients through the internalization and degradation of AM. Recently, the Caron laboratory identified a novel interaction between ACKR3 and receptor-activity-modifying protein 3 (RAMP3). They showed in vitro that RAMP3 is required for the recycling of ACKR3 to the plasma membrane after AM-stimulated internalization and that loss of ACKR3 or RAMP3 in vivo results in impaired vascular development. However, the mechanism by which RAMP3 regulates ACKR3 activity and signaling in lymphatic endothelial cells (LECs) and the process of lymphangiogenesis remains unknown. RAMP3 is unique among the RAMPs in that it contains a C-terminal PDZ motif that mediates its function by promoting protein-protein interactions with PDZ domain-containing proteins. Therefore, the overarching hypothesis of this training proposal is that RAMP3 and its PDZ motif enhances ACKR3 activity and signaling within LECs to regulate lymphangiogenesis. Completion of this proposal will define the role of RAMP3 in the regulation of ACKR3 signaling and lymphangiogenesis, thereby advancing the current knowledge of the lymphatic biology field. In addition, this proposal will provide invaluable experience and training in the performance of ethical and rigorous research and effective scientific communication.