# The protective role of kidney-derived Tamm Horsfall protein (Uromodulin) in sepsis

> **NIH NIH K99** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $91,500

## Abstract

This K99/R00 application from Kaice A LaFavers, PhD, is designed to acquire the knowledge and
training necessary to transition to an independent faculty position leading a research program
focused on kidney-organ cross talk in the setting of sepsis and severe infection. Sepsis is a
dysregulated host response to infection and is a major contributor to morbidity and mortality
worldwide. When acute kidney injury (AKI) occurs in the setting of sepsis, mortality doubles to
approximately 1 in 2 patients. We have recent evidence that the kidney-derived Tamm Horsfall
Protein (THP) is protective against sepsis mortality. THP is secreted from the kidney primarily into the
urine, where it is the most abundant protein component. However, a small portion of THP produced in
the kidney is secreted into the kidney interstitium, where it enters the circulation. Increased levels of
serum THP have recently been associated with decreased mortality and protection against chronic
kidney disease in human cohorts. Circulating THP has also emerged as an immune regulator, with
genetic depletion of THP leading to decreased number and function of mononuclear phagocytes in
the kidney. In both human and animal models of AKI, THP is acutely depleted shortly following injury.
In the current proposal, the overall hypothesis is that the kidney protects other organs during sepsis
by releasing THP in the circulation, where it enhances macrophage function and signaling. This
hypothesis will be tested by two specific aims. One aim will establish that circulating THP released by
the kidney is a key protective molecule in sepsis using a genetic knockout model of THP depletion in
murine sepsis. This aim will also determine the potential of treating septic mice with exogenous THP
to improve sepsis outcomes. The second aim will define the effect of THP on enhancing macrophage
function by assessing in vivo phagocytosis, macrophage activation and signaling, and macrophage-
derived IL-15-dependent signaling in sepsis. Under the mentorship of Dr. Tarek Ashkar, Dr. LaFavers
extends her current research on THP biology and proposes additional training. This additional training
will be in the areas of technical skill development, including bioinformatics, advanced imaging
analytics, protein purification, mouse model development and breeding, along with professional
career development in science communication, lab management, grant/manuscript writing and
mentoring. The completion of this proposal will provide Dr. LaFavers with the expertise and training
for her first R01 submission and the establishment of an independent career.

## Key facts

- **NIH application ID:** 10301616
- **Project number:** 1K99DK127216-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Kaice LaFavers
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $91,500
- **Award type:** 1
- **Project period:** 2021-08-10 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301616

## Citation

> US National Institutes of Health, RePORTER application 10301616, The protective role of kidney-derived Tamm Horsfall protein (Uromodulin) in sepsis (1K99DK127216-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10301616. Licensed CC0.

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