# Calcium-dependent autoregulation of vasopressin neurons in a rodent model of heart failure.

> **NIH NIH K99** · GEORGIA STATE UNIVERSITY · 2024 · $94,840

## Abstract

PROJECT SUMMARY
This K99/R00 proposal will test a critical hypothesis on how vasopressin (VP) neurons self-regulate their neuronal
excitability, their local paracrine release of vasopressin, and how these mechanisms are altered in a rodent model of
heart failure while providing the PI with additional scientific and professional skills to transition him to a successful
independent career as a research professor.
Heart failure (HF) is the leading cause of death worldwide. A hallmark of HF is sympathetic hyperactivity and increased
circulating levels of neurohormones such as VP. The slow afterhyperpolarization (sAHP) is recognized as a key mechanism
that influences VP firing, playing a critical role in shaping the stereotyped phasic bursting patterns in VP neurons. The
sAHP is impaired in VP HF neurons. Uniquely, Ca2+-dependent exocytosis of VP occurs somatodendritically (VP-SDR) as
well, acting in a paracrine manner as an auto-inhibitory feedback mechanism. It is currently unknown whether VP-SDR is
impaired in VP HF neurons. Data presented herein shows sAHPs and VP-SDR share many common signaling pathways
which have been observed separately but never in tandem. Furthermore, we have exciting preliminary data that demonstrates
VP itself can enhance isolated sAHPs, suggesting that endogenous VP-SDR may modulate sAHP time course, and thus
firing activity. Understanding how these mechanisms lead to aberrant VP neuronal activity in HF is of critical importance.
I therefore present the unique hypothesis that sAHP and VP-SDR activation are not only activated by the same
signaling and pathways, but that VP-SDR can directly modulate sAHPs. I hypothesize that the observed impairment
of the sAHP in HF neurons reflects impaired intracellular Ca2+ signaling and VP-SDR, leading to the
hyperexcitability and excess peripheral VP release observed in this condition. Aim 1 will test the hypothesis that certain
modes of VP activation (ex. continuous vs. phasic stimulation) favors the activation of either sAHPs or VP-SDR. Aim 2
will test the hypothesis that endogenous VP-SDR itself modulates sAHPs. Aim 3 will test the hypothesis that intracellular
Ca2+ sensitivity/availability and VP-SDR are impaired in VP neurons of HF rats. This proposal will significantly enhance
the PI’s career development and advance him towards his goal of becoming an independent investigator. The proposed
project provides training in technical skills and professional development with an emphasis on independence and acquiring
skills needed to run a laboratory. We will accomplish this by uniquely integrating previously mastered techniques in a novel
way to measure sAHPs and VP-SDR simultaneously via patch clamp and utilization of VP detecting “sniffer” cells,
respectively from healthy and HF rats. Georgia State University also provides an exceptional environment for training with
the facilities and equipment needed to perform the research, an intellectual environment of seminars and workshops,
ongo...

## Key facts

- **NIH application ID:** 10844644
- **Project number:** 5K99HL168434-02
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Matthew Kirchner
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $94,840
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844644

## Citation

> US National Institutes of Health, RePORTER application 10844644, Calcium-dependent autoregulation of vasopressin neurons in a rodent model of heart failure. (5K99HL168434-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10844644. Licensed CC0.

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