# Interplay between skeletal muscle catabolism and remodeling of arteriovenous fistulae via YAP1/TAZ signaling

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $412,573

## Abstract

Summary
 Arteriovenous fistula (AVF), an artificially created direct connection between an artery and
vein, is the life line for hemodialysis patients suffering from chronic kidney disease (CKD).
However, 60-65% of AVFs fail within 1 year of their creation resulting in serious health risks and
heavy financial burden to patients. The costs of placing or caring for vascular access exceed $2.8
billion/year. Although, multiple clinical trials have been performed, no viable treatment options
have been uncovered. Our long term goal is to identify the cellular and molecular mechanisms of
AVF maturation failure so that therapeutic strategies can be developed to prevent and treat AVF
failure. Earlier studies demonstrated that CKD-induced neointima (thickening of inner vascular
layer) formation and vascular fibrosis are the leading risk factors causing AVF maturation failure.
Recently, we found the crosstalk between skeletal muscle catabolism in uremic mice could be
related with AVF function failure. Our Preliminary results indicated that myostatin generated in
skeletal muscle in uremic mice stimulated the expression of YAP1/TAZ (transcriptional regulators
of genes involved in cellular proliferation) which can promote activation of vascular smooth muscle
cells (VSMCs) and differentiation of adventitial mesenchymal stem cells (MSCs) into
myofibroblasts. These responses result in increased extracellular matrix proteins and progressive
vascular fibrosis. The stiffness of extracellular matrix activates YAP1/TAZ which forms a “forward
feedback loop”. The result is the enhanced proliferation, migration, and inflammation which lead
to AVF maturation failure. We therefore hypothesize that inhibition of myostatin or of YAP1/TAZ
will block VSMC activation and MSC differentiation into myofibroblasts resulting in improved AVF
functions. Specific Aims proposed in this application will investigate the validity of this hypothesis.
In Aim 1 we will examine the effects of myostatin inhibition using a neutralizing peptibody on
neointima cells and AVF fibrosis in CKD mice. Aim 2 and 3 will analyze the effects of YAP1 and
TAZ knock down on myostatin induced VSMC activation and MSC transdifferentiation in vitro and
in vivo, and evaluate if local inhibition of YAP1 activation by FDA-approved drug, Verteporfin
suppresses CKD–induced AVF failure in mice. Successful completion of these studies will lead
to the development of new therapeutic strategies to prevent and treat AVF failure in dialysis
patients.

## Key facts

- **NIH application ID:** 10113606
- **Project number:** 5R01DK124259-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jizhong Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,573
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113606

## Citation

> US National Institutes of Health, RePORTER application 10113606, Interplay between skeletal muscle catabolism and remodeling of arteriovenous fistulae via YAP1/TAZ signaling (5R01DK124259-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113606. Licensed CC0.

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