# Blocking Latent TGF-β2 Activation as a Therapeutic Strategy for Renal Fibrosis

> **NIH NIH K01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $155,346

## Abstract

ABSTRACT. Transforming growth factor beta2 (TGF-β2) is an important therapeutic target for renal fibrosis, the
principal cause of end-stage renal failure in chronic kidney disease (CKD). TGF-β2 triggers renal fibrosis in vivo
and, in response to kidney injury, is upregulated in renal myofibroblasts, pericytes, and proximal tubule epithelial
cells—cell types that mediate kidney fibrosis. Earlier studies showed that an antibody to mature TGF-β2 arrested
renal fibrosis in a rat model of diabetic kidney disease, but further therapeutic development was not followed up.
In vivo, TGF-β2 exists mainly as a latent pro-complex (proTGF-β2) in which prodomains are noncovalently bound
to the growth factor. Secreted proTGF-β2 is stored in different extracellular milieus where it undergoes activation,
i.e. release of the growth factor (mature TGF-β2), to initiate signaling. Preliminary data point to αVβ6-dependent
and -independent mechanisms of proTGF-β2 activation as different modalities that can be therapeutically
targeted for renal fibrosis. Aim 1 of this proposal is to develop new antibodies that specifically target the
prodomain and block proTGF-β2 activation as a novel therapeutic strategy for renal fibrosis. Antibodies will be
selected from an innovative yeast display antibody library, screened for activation-blocking activity in vitro, and
tested for therapeutic efficacy in mouse models of acute kidney injury. Aim 2 is to determine high-resolution
crystal structures of proTGF-β2 to define the mechanism underlying latency and facilitate drug development by
uncovering new strategies to prevent activation. The candidate has assembled an exceptional team of mentors
and advisors with expertise in renal pathophysiology, drug discovery, and structural biology to ensure the
success of the project. The team will provide career guidance and training in techniques essential for the
candidate’s future independent career at the interface of structural biology, drug discovery, renal fibrosis, and
CKD. The candidate will receive extensive training in 1) X-ray crystallography, 2) antibody discovery, 3) renal
pathophysiology, 4) immunofluorescence microscopy, and 5) mouse models of acute kidney injury and renal
fibrosis. These skills will extend the candidate’s already versatile foundation in genetics, molecular biology,
protein biochemistry, and structural biology. Boston Children’s Hospital and surrounding institutions (e.g.,
Harvard Medical School) constitute a robust training environment with unparalleled intellectual capital and
remarkable infrastructure, which include cutting-edge yeast display platforms for antibody discovery at the
Institute for Protein Innovation and unparalleled resources and expertise in the Renal Division at Brigham and
Women’s Hospital, that will enhance the candidate’s growth and support his proposed research. Career
development will be accomplished through direct mentorship, education through fellowship training offices, and
attendance of...

## Key facts

- **NIH application ID:** 10215977
- **Project number:** 1K01DK124443-01A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Viet Quoc Le
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $155,346
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215977

## Citation

> US National Institutes of Health, RePORTER application 10215977, Blocking Latent TGF-β2 Activation as a Therapeutic Strategy for Renal Fibrosis (1K01DK124443-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10215977. Licensed CC0.

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