# Thrombin-Mediated Podocyte Injury Mechanisms

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2022 · $444,624

## Abstract

PROJECT SUMMARY/ABSTRACT
Nephrotic syndrome is a leading cause of end stage kidney disease, which is the eighth leading cause of death
in the United States. Thrombin injures podocytes and its inhibition reduces nephrotic-range proteinuria and
podocyte injury, two key drivers of nephrotic syndrome progression toward end stage kidney disease. Thus,
there is a critical need to discern the molecular mechanisms underlying thrombin-mediated podocyte injury
without which, the development of targeted, safe, and effective therapies that slow or halt nephrotic syndrome
progression is likely to remain limited. The overall objective of this proposal is to define molecular mechanisms
underlying thrombin-dependent, protease-activated receptor-mediated podocyte injury and determine if inhibition
of this signaling pathway reduces progression toward end stage kidney disease. The central hypothesis is that
thrombin-mediated protease-activated receptor signaling is a modifiable driver of RhoA-dependent podocyte
injury during nephrotic syndrome progression. This project will integrate methods from the podocyte and
coagulation biology fields including: mouse and rat nephrotic syndrome models, coagulation factor knockdown
and conditional protease-activated receptor knockout mice, innovative nanoparticle-mRNA overexpression of
coagulation factors, repurposing of Food and Drug Administration approved direct oral anticoagulants to mitigate
podocyte injury, a novel flow cytometry approach to quantitate podocyte injury, and molecular biology methods
including bimolecular fluorescence complementation and bioluminescence resonance energy transfer in
genetically modified podocyte cultures. These complementary methods will be used to investigate the
pathophysiologic role of thrombin in podocyte injury and nephrotic syndrome progression toward end stage
kidney disease. Our Aims are designed to (1) Reveal the prothrombinase that produces intraglomerular,
podocytopathic thrombin to drive podocyte injury and nephrotic syndrome progression, (2) Test the ability of
direct oral anticoagulant therapy as a novel method to reduce nephrotic syndrome progression, and (3) Discover
the molecular mechanisms by which thrombin-mediated protease-activated receptor signaling stimulates RhoA-
dependent podocyte injury. This project is directly responsive to the mission of the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK) which is to “…support medical research…on kidney…and
hematologic diseases, to improve people’s health and quality of life.” In addition, this project directly addresses
important research priorities described in the Kidney Research National Dialogue and key aspects of the Healthy
People 2030 Chronic Kidney Disease objectives. Completion of the proposed project is expected to establish
the mechanisms underlying thrombin-mediated podocyte injury and enable exploitation of existing, Food and
Drug Administration approved, direct oral anticoagulants as novel...

## Key facts

- **NIH application ID:** 10492590
- **Project number:** 5R01DK124549-02
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Bryce Andrew Kerlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,624
- **Award type:** 5
- **Project period:** 2021-09-22 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492590

## Citation

> US National Institutes of Health, RePORTER application 10492590, Thrombin-Mediated Podocyte Injury Mechanisms (5R01DK124549-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10492590. Licensed CC0.

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