# A mechanistic approach to intercalated cell phagocytosis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $625,300

## Abstract

PROJECT SUMMARY/ABSTRACT
Pyelonephritis continues to result in considerable morbidity, mortality, and health care expense. To develop new
treatment strategies, a more thorough understanding of the kidney’s innate defense is needed.
Our research has identified a murine intercalated cell deficiency model that is susceptible to pyelonephritis. We
have also demonstrated that human and murine intercalated cells produce and secrete antimicrobial peptides.
Others have demonstrated that intercalated cells act as the first site in the kidney that responds to Gram-negative
organisms via pattern recognition receptor signaling pathways. Thus, surmounting evidence suggests that
intercalated cells perform a critical role in the innate defense of the kidney.
In this proposal, our research team builds on our findings from our recent Nature Communications manuscript
and a prior R01 intercalated cell (IC)-focused grant. We have previously demonstrated that innate immune gene
expression is enriched in intercalated cells and alterations of intercalated cells lead to increased urinary tract
infection (UTI) susceptibility. Next, we performed single cell mRNA sequencing and biological pathway analysis
on human kidneys following stimulation with uropathogenic E. coli. “Phagosome maturation” was a key
intercalated cell pathway, particularly after exposure to bacteria that cause UTIs. More recently, we have
developed preliminary data that demonstrates that IC phagocytosis is dependent on Signal transducer and
activator of transcription 3 (Stat3) signaling.
We hypothesize that intercalated cells Stat3 related phagocytic functions are activated via Toll like receptor 4
(Tlr4) and Janus kinase (Jak1) signal transducers and subsequently control acid secretion into the cellular
compartments that contain internalize bacteria (phagosomes). To build on our previous studies, we have devised
three specific aims that will thematically examine the role of intercalated cells in innate defense of the kidney.
We know that intercalated cells can phagocytose bacteria. In Specific Aim 1, we will determine the extent that
the Stat3 IC signaling pathway is dependent on upstream Tlr4 and or Jak1. In Specific Aim 2, we will determine
the extent that Stat3 regulates kidney control of phagosome pH. Finally, in Specific Aim 3, we will look at the
functional consequences of increasing Stat3 activation on the IC phagocytosis and the kidney burden during
experimental pyelonephritis.
Our long-term research goal is to develop new pyelonephritis treatment strategies that reduce antibiotic exposure
and preserve kidney function in populations at risk. This research will provide the foundation to include
modulation of intercalated cells in pyelonephritis management, thereby expanding treatment scope beyond
antibiotics.

## Key facts

- **NIH application ID:** 10882212
- **Project number:** 1R01DK136510-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** David Sullivan Hains
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,300
- **Award type:** 1
- **Project period:** 2024-08-11 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882212

## Citation

> US National Institutes of Health, RePORTER application 10882212, A mechanistic approach to intercalated cell phagocytosis (1R01DK136510-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10882212. Licensed CC0.

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