# Role of Collagen Binding Receptors in Glomerulosclerosis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Abstract
Glomerulosclerosis is one of the hallmarks of end stage kidney disease and it is characterized by the
replacement of the glomerular tissue with extracellular matrix components (mainly collagens) leading to the
loss of functioning glomeruli. The goal of this grant is to investigate the molecular mechanisms that underlie
the modulation of collagen turnover in injured glomeruli to devise more effective therapies to prevent
glomerulosclerosis. Although many pathways have been implicated in both initiation and progression to
glomerular fibrosis, we focus on the collagen binding receptor integrin α1β1 (Itgα1β1). This receptor plays an
anti-fibrotic action by recruiting and activating the tyrosine phosphatase TCPTP thus downregulating the
phosphorylation of pro-fibrotic receptors, including the EGF receptor (EGFR). Moreover, Itgα1β1 negatively
regulates collagen levels at both transcriptional and translational levels.
Recently, we started to investigate the mechanisms whereby Itgα1β1 controls collagen synthesis at the nuclear
level. As nuclear translocation and activation of many transcription factors and/or ribonucleoproteins are
regulated by tyrosine phosphorylation, we analyzed the levels of tyrosine phosphorylated nuclear proteins in
wild type and Itgα1KO mesangial cells to identify proteins tyrosine phosphorylated only in Itgα1KO cells. We
identified the ribonucleoprotein Fused in Sarcoma (FUS) as a candidate. We show that in Itgα1KO mesangial
cells, increased levels of total and tyrosine phosphorylated nuclear FUS are associated with increased
collagen production and downregulation of FUS decreases collagen synthesis. Interestingly, FUS contains two
tyrosines that can be phosphorylated by EGFR and dephosphorylated by TCPTP and the levels of nuclear
FUS are associated with levels of activated EGFR. Based on these observations and the finding that FUS is
upregulated in injured human and mouse kidneys, we propose that FUS is a positive regulator of collagen
synthesis and plays a pro-fibrotic action in the course of glomerulosclerosis. We hypothesize that Itgα1β1
negatively regulates FUS tyrosine phosphorylation and function in an EGFR-dependent and -
independent manner. Thus, Itgα1β1-mediated dephosphorylation of FUS represents an important, but
previously undescribed mechanism to selectively reduce FUS activation and consequent progression to
fibrosis. The aims of this grant are designed to define the contribution of FUS to glomerular disease and to
determine whether blocking its function is beneficial for the treatment of glomerulosclerosis.
In Aim 1 we will determine in vitro the mechanisms whereby FUS transcriptionally controls collagen production
and determine whether inhibiting FUS ameliorates collagen synthesis. In Aim 2 we will determine the role of
FUS in the progression to glomerular injury using a genetic and pharmacological approach. We will investigate
the response of wild type and Itgα1KO mice crossed with global FUSKO mice, as...

## Key facts

- **NIH application ID:** 10047698
- **Project number:** 5I01BX002025-08
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** AMBRA POZZI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047698

## Citation

> US National Institutes of Health, RePORTER application 10047698, Role of Collagen Binding Receptors in Glomerulosclerosis (5I01BX002025-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047698. Licensed CC0.

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