# Signaling and Function of the Adrenal Rosette

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $488,869

## Abstract

Project Summary: Autonomous aldosterone production is emerging as a significant clinical problem. It is
not regulated by salt status or the renin-angiotensin system. Autonomy is severe in primary aldosteronism,
prevalent in low-renin and resistant hypertension, and subtle but evident in normotension. When
inappropriate for salt status, aldosterone promotes cardiovascular disease. The central premise of this
application is that the anatomical, rosette-like organization of aldosterone producing cells (zona Glomerulosa,
zG) within the adrenal cortex dictates their cellular behavior. Thus, understanding how zG cell behavior is
controlled by the rosette structure will reveal ways to control autonomous aldosterone production that at
present do not exist.
Previously, we discovered that zG cells behave as electrical oscillators when their cellular connectivity is
maintained within rosettes. Using genetically encoded Ca2+ indicators, we have built on this discovery and now
provide exciting preliminary data identifying one potential new target, the TRPV4 channel, and one potentially
new mode for zG cell activation, mechanoactivation. Our overall hypothesis is that TRPV4 activity in rosettes
sets the limits of zG cell excitability. We further propose that this TRPV4 activity is controlled by second
messengers, mechanical stimuli and cadherin-mediated adhesion, thus providing additional ways of regulating
zG cell behavior.
In Aim 1 of this proposal we seek to establish the role of TRPV4 activity in voltage and Ca2+ oscillations in zG
cells using high speed imaging tools and all optical electrophysiology. In Aim 2 of this proposal we seek to
determine how adherens junctions (AJ) recruit and control coordinated Ca2+ signals among zG cells within
rosettes. We will target the LGR4/5 or ROBO1/3 signaling pathways to dynamically regulate the
integrity/composition of the AJ complex (N-cadherin/β-catenin/α-catenin/vinculin/actin) and assess resulting
Ca2+ signals. In Aim 3 of this proposal we seek to determine how adherens junctions facilitate autonomous
aldosterone production evoked by mechanoactivation and how these junctions also enhance the steroidogenic
sensitivity to Ang II. We measure two steroidogenic indices: aldosterone and NAD(P)H generation.
This project will be conducted using advanced, high-resolution, epifluorescence/confocal imaging methods
with genetically encoded probes, state-of-the-art image analysis and biochemical, molecular and
electrophysiology methods. This research is expected to (1) discover how the rosette organizes cellular activity
within the zG layer and, (2) identify new mechanisms and therapeutic targets that can be exploited to control
aldosterone autonomy.

## Key facts

- **NIH application ID:** 10131837
- **Project number:** 5R01HL138241-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** NICK Anthony GUAGLIARDO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $488,869
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131837

## Citation

> US National Institutes of Health, RePORTER application 10131837, Signaling and Function of the Adrenal Rosette (5R01HL138241-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10131837. Licensed CC0.

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