Characterization of Novel Signaling Pathways Involved in Water Balance Disorders

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PROJECT SUMMARY/ABSTRACT Maintenance of water homeostasis is a vital function of the kidneys and is essential for adaptation to terrestrial life. To reabsorb water effectively, vasopressin (VP) is released to induce aquaporin-2 (AQP2) phosphorylation and actin cytoskeletal remodeling within kidney principal cells in the collecting ducts, which increases apical membrane expression of AQP2. Dysregulation of AQP2 trafficking results in disorders of water balance; decreased AQP2 membrane expression causes nephrogenic diabetes insipidus (NDI), whereas an increase in plasma membrane AQP2 is associated with fluid retention in the syndrome of inappropriate ADH secretion (SIADH), congestive heart failure and cirrhosis. While VP/cAMP/PKA is the major signaling pathway that facilitates AQP2 membrane trafficking and water reabsorption, the process is in fact far more complex, and can be induced or inhibited by other signaling pathways. One such “alternative” pathway involves the epidermal growth factor receptor (EGFR), whose inhibition induces AQP2 membrane accumulation and phosphorylation similar to VP, but bypasses V2R, cAMP and PKA, and my goal is to deepen our understanding of the crosstalk between VP and EGFR pathways that modulate AQP2, with a long term career goal to characterize the role of this novel signaling pathways in dysregulated water retention observed in patients with SIADH, congestive heart failure and liver cirrhosis, in order to eventually design therapies to alleviate disease symptoms encountered in the clinic. For the last year and a half, I have been making significant progress in dissecting the pertinent pathways between VP and EGFR that regulate water balance. However, as I am focusing on my research career development, life not only brings us surprises, but also concerns about interruption in research progress. Therefore, I am applying for this new NIH-NIDDK Administrative Supplement in order to hire a technician during my maternity leave, expected to span between early to mid-July to early October 2020, in order to preserve or even increase research productivity. The Brown Laboratory, including my mentor Dr. Dennis Brown, my close collaborator Dr. Richard Bouley, and I will maximize the intellectual and technical resources to ensure progress during my leave, and I will remain updated on the progress to resume full productivity upon my return. This research proposal is carved out of Aim 1 of my parent K08, and the proposed experiments are carefully designed and expected to be completed by the end of the supplemental period. Obtaining this supplement funding would provide highly valuable support at this critical time of my research career.