# Characterization of Novel Signaling Pathways Involved in Water Balance Disorders

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $172,800

## Abstract

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. Therefore, the aims of this grant are to 1) define the
mechanism of crosstalk between VP and EGFR signaling pathways that regulate AQP2 trafficking; 2)
understand the role of AQP2 phosphorylation on cytoskeletal remodeling, and 3) characterize the roles of
novel signaling pathways in dysregulated water retention observed in patients with congestive heart failure, in
order to eventually design therapies to alleviate disease symptoms encountered in the clinic.
The training plan is progressive and is designed to move the PI Dr. Cheung through an initial stage of
completing and expanding her exciting, ongoing work on EGF/VP crosstalk (Aim 1), then moving on to a new
aspect of AQP2 cytoskeletal interactions not so far examined in the lab (Aim 2), before finally arriving at Aim 3
on heart/kidney interactions and water balance, which will complete her pathway to independence and be the
subject of her first R01 application. Dr. Cheung, supervised by her mentor Dr. Brown, will not only employ
existing technologies in the Program in Membrane Biology, but will also acquire important new techniques and
research training both from courses listed in her personalized training plan, and from the experts on her
advisory committee Drs. Joung (CRISPR/Cas9 gene editing) and Nahrendorf (surgery and mouse imaging for
heart failure). For professional career development, in addition to her award-winning mentor Dr. Brown, she
has Drs. Sylvie Breton and Jodie Babitt as successful female academic scientist role models. Moreover, the
MGH Nephrology Division chief, Dr. Ravi Thadhani will protect her research time from clinical duties, allowing
full immersion in her research. Her mentor, members of her scientific advisory committee, her Division chief,
the nurturing and collaborative environment in the MGH and Harvard community, will combine with a careful...

## Key facts

- **NIH application ID:** 9979859
- **Project number:** 5K08DK115901-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Pui Wen Cheung
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $172,800
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979859

## Citation

> US National Institutes of Health, RePORTER application 9979859, Characterization of Novel Signaling Pathways Involved in Water Balance Disorders (5K08DK115901-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9979859. Licensed CC0.

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