The role of apelin receptor signaling in lymphatic vessel

About This Grant

Project Summary: Mechanical forces, including extrinsic compression from surrounding tissues and intrinsic pressures such as wall shear stress (WSS), are critical for normal lymphatic functions, which are essential in maintaining fluid homeostasis, trafficking immune cells, and absorbing intestinal lipids. Dysfunction of lymphatic vessels can lead to disabling and sometimes life-threatening tissue swelling known as lymphedema (LD). An estimated 250 million individuals worldwide suffer from LD, yet no effective treatments are currently available. Apelin, through activation of its receptor, Apelin Receptor (APJ, gene APLNR), is an emerging effective treatment for LD in humans. APJ can be activated by ligands, Apelin and Elabela (ELA), and by mechanical forces. APJ signaling is critical in regulating lymphatic functions such as lymphatic vessel development, vasodilation, and restores lymphatic function, but the precise coordination of receptor ligand-mediated signaling and mechanotransduction to govern the protective effects of APJ remain unclear. Therefore, my central hypothesis is that integrated APJ signaling— activated by both ligands and mechanical forces—is critical for maintaining the normal physiological function of lymphatic vessels. Results from my studies will provide mechanistic characterization of APJ signaling in the lymphatic system, laying the foundation for its therapeutic potential in LD, including ongoing clinical trials. The training opportunities in this proposal have expansive translational value for the treatment of LD and will facilitate successful transition of Dr. Yanna Tian’s career from a postdoctoral fellow to an independent researcher. Dr. Kathleen M. Caron, a world-renowned scientist specializing in GPCR signal transduction and lymphatic vessel biology, will support this proposal and mentor Dr. Tian’s scientific and career development, facilitating her transition to independence throughout this award. To enhance training, Dr. Caron and Dr. Tian have established an advisory mentoring team, comprising Drs. Dixon, Polacheck, and Kim, and external consultant, Dr. Garmy- Susini, who will provide expertise across all relevant areas of this proposal. The supportive research environment, with the NIH Pathway to Independence Award (K99/R00), will facilitate a successful transition of Dr. Tian’s career to a competitive and independent tenure-track research position.