# Protein Nutrition in Experimental Uremia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $348,000

## Abstract

Project Abstract
 Protein-Energy Wasting (PEW) is a prevalent complication in chronic kidney disease (CKD),
leading to muscle wasting and significantly contributing to morbidity and mortality. Maintaining
skeletal muscle homeostasis and function is essential for CKD patient care. However, the precise
mechanisms causing muscle wasting and the development of effective therapeutic strategies
remain under investigation.
 We aim to pinpoint the CRL4ACRBN ubiquitin E3 ligase as a novel catabolic mediator
responsible for muscle protein loss in CKD. Our initial findings indicate that the CRL4ACRBN E3
ligase is activated in CKD mouse muscles. Targeted disruption of this ligase in muscles
effectively counters CKD-induced muscle wasting. Using tandem-affinity purification of
ubiquitinated proteins combined with quantitative mass spectrometry, we identified two potential
CRL4ACRBN E3 ligase targets: ovarian tumor deubiquitinase 7B (OTUD7B) and peroxiredoxin-5
(PRDX5). OTUD7B is an enzyme that inhibits TRAF7-induced NF-kB signaling, while PRDX5 is
recognized for its protective role against mitochondrial-associated oxidative stress. In human
skeletal muscle cell cultures, we noted that pomalidomide, a CRL4ACRBN E3 ligase inhibitor,
counters cytokine-induced reductions in OTUD7B and PRDX5. This intervention results in the
suppression of atrogene expression, proteolysis, and oxidative stress.
 From these observations, we hypothesize that activating CRL4ACRBN E3 ligase hastens the
degradation of OTUD7B and PRDX5, amplifying atrogene expression and oxidative stress.
Conversely, inhibiting this E3 ligase should deter catabolic signaling and combat oxidative stress,
thereby curbing the onset of muscle wasting in CKD. In this proposal, we plan to employ multi-
omics methods, transgenic models, and a humanized mouse model to address three pivotal
questions: How does CKD activate the CRL4ACRBN E3 ligase in muscles? Through what
mechanisms does it exacerbate muscle wasting? Can the FDA-approved drug, pomalidomide,
reverse CKD-induced muscle wasting? Our research could unveil novel pathways implicated in
muscle wasting and showcase the promise of drug repurposing as a cost-effective and efficient
means for devising viable therapeutic strategies.

## Key facts

- **NIH application ID:** 10979023
- **Project number:** 2R01DK037175-36A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zhaoyong Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $348,000
- **Award type:** 2
- **Project period:** 1987-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979023

## Citation

> US National Institutes of Health, RePORTER application 10979023, Protein Nutrition in Experimental Uremia (2R01DK037175-36A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10979023. Licensed CC0.

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