Salt, Diet & Hypertension: An integrative in vivo physiological investigation of WNK pathway controlled renal electrolyte and blood pressure homeostasis. (360G-Wellcome-110282_Z_15_Z)

This project is designed to directly address a technique/technology gap that has prevented us from answering key biomedical questions in WNK controlled cardio-renal physiology. By modular combination of existing techniques/technologies the project puts forth a novel strategy to address the lack of direct, tubular segment-specific measurements of the renal physiology in vivo that may be integrated with other primary data. By the end of the project several outstanding biomedical questions in field of WNK biology and electrolyte homeostasis will have been directly addressed for the first time, and the first integrated map of distal convoluted tubular functional will have been produced. Key goals: 1) Develop an in vivo technique to simultaneously quantify renal tubule ion transport and intracellular chloride and pH by combining live imaging of GFP-based biosensor transgenic mice and micropuncture/perfusion techniques. 2) Integrate tubular ion transport functional readouts with bio chemical and morphological data obtained from microdissected tubule segments and whole tissue 3D fluorescent imaging using the CLARITY technique. 3) Validate the current model (Figure 2) used to explain the relationship between blood potassium levels, intracellular chloride, WNK/SPAK/NCC activity and blood pressure; reconcile the model with the paradoxes presented by Gordon and Gitelman syndrome.