# Molecular Basis of Renal Epithelial Cell-Cell Adhesion

> **NIH NIH F30** · STANFORD UNIVERSITY · 2021 · $39,670

## Abstract

Project Summary
 The goal of this project is to determine how renal tubular epithelial cells achieve robust cell-cell adhesion
when faced with external forces. In the kidney, this occurs regularly as volume fluctuations distend the urinary
collecting system to varying degrees. An extreme example occurs in autosomal-dominant polycystic kidney
disease (ADPKD), the most common inherited renal disorder, where renal cysts can endure 1000-fold strain in
diameter, but can rupture upon acute trauma, leading to other serious consequences.
 Approximately 85% of ADPKD cases are caused by mutations in the protein polycystin-1 (Pc-1), a
putative atypical G-protein coupled receptor that is involved in intracellular signal transduction via sequestration
of the G protein subunit G12. Relatively little is known about how dysregulated G12-mediated signaling in
ADPKD leads to the physical compromise of cell-cell adhesion. This gap persists, in part, because even simple
questions remain unanswered about how epithelial cells mechanically regulate cell-cell adhesions under strain.
This proposal will address two such fundamental questions, using the case of ADPKD as a concrete example of
how such regulation may be disrupted. To do so, I will make use of a semi-reconstituted system in which Madin-
Darby Canine Kidney (MDCK) epithelial cells form junctions with supported lipid bilayers (SLBs) decorated with
the cell adhesion molecule E-cadherin. This system enables both high resolution microscopy on live cells and
precise application of externally applied forces using magnetic tweezers.
 Aim 1 will address the question of how cells ensure robust adhesion using the E-cadherin molecules that
bind between cells. High resolution total internal reflectance fluorescence (TIRF) and reflectance interference
contrast (RICM) imaging will be used to visualize the clustering of E-cadherin and the cell-SLB distance,
respectively, as a function of applied force. Aim 2 will address the question of how cells transmit external loads
through the collection of E-cadherin molecules. Fluorescent single-molecule tension sensors will be used to
directly measure single-molecule force distributions as a function of externally applied load. Finally, Aim 3 will
systematically perturb the Pc-1/G12 signaling axis to determine how cadherin-mediated adhesion and force
transmission may be dysregulated in ADPKD.
 The results of this work will determine how signaling downstream of Pc-1 may contribute to the
dysregulation of cell-cell adhesion in ADPKD, and, more broadly, reveal the biophysical mechanisms that
epithelial cells use to maintain robust cell-cell adhesion even in the face of sometimes extreme external forces.
When combined with a research training plan emphasizing development in research communication and
incorporating continued clinical experience, this work will prepare me to pursue further training towards a career
as an independent physician-scientist studying disrupted tissue architec...

## Key facts

- **NIH application ID:** 10124048
- **Project number:** 5F30DK124985-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Vipul Vachharajani
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,670
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124048

## Citation

> US National Institutes of Health, RePORTER application 10124048, Molecular Basis of Renal Epithelial Cell-Cell Adhesion (5F30DK124985-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124048. Licensed CC0.

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