# Lymphatic ERG signaling in scleroderma fibrosis

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $621,218

## Abstract

SSc is characterized by autoimmunity, small blood vessel vasculopathy, and fibrosis causing damage in
multiple organ systems. Current evidence posits that SSc originates from the endothelial injury, and if vascular
neoangiogenic response fails to repair the damage, downstream pathological fibrosis ensues. Analogous to the
blood vascular system, rarefaction of lymphatic vessels has also been documented in SSc patients. In contrast
to the blood endothelium, the molecular mechanisms governing the lymphatic system defects remain largely
unexplored. Our overarching goal is to delineate the molecular and cellular mechanisms that drive impairment
of blood and lymphatic systems in SSc. To improve treatment options for SSc vascular disease, there is an
urgent need in uncovering new molecular targets. The signaling molecules that selectively regulate deficiency of
both blood and lymphatic endothelial cells would be desirable targets for therapeutic intervention. Furthermore,
although there is increased evidence of impaired lymphatic circulation, there have been no studies that
addressed the mechanisms responsible for the impairment of the lymphatic system in SSc. Based on published
and our new preliminary data, we hypothesize that transcription factors ERG is required for regeneration of
lymphatic vasculature and its deficiency leads to impaired wound healing and fibrosis. Furthermore, we
hypothesize that deficiency of ERG is a shared pathological feature, yet with critical variations, between blood
and lymphatic endothelial cells in SSc patients, which may contribute to impaired angiogenesis and
lymphangiogenesis in these patients. We propose to use a comprehensive strategy, including analysis of gene
expression in freshly isolated BEC and LEC from SSc and control skin biopsies, together with our newly
developed mouse models of SSc vasculopathy based on the postnatal deletion of Erg in blood and lymphatic
cells, and mechanistic in vitro studies to molecularly and functionally characterize the role of ERG deficiency in
blood and lymphatic systems. We propose the following three aims: In Aim 1 we will investigate the role and
functional significance of ERG deficiency in LEC focusing on the signaling pathways controlling proliferation; In
Aim 2 we will use lineage tracing to determine the functional consequences of Erg endothelial deficiency during
physiological neo-angiogenesis and neo-lymphangiogenesis; In Aim 3 we will determine if Erg lymphatic
deficiency leads to increased susceptibility to fibrosis. If successful, the proposed study has the potential to
establish new basic knowledge pertinent to lymphatic cell function and dissect novel mechanism(s) driving SSc
lymphangiopathy.

## Key facts

- **NIH application ID:** 10435724
- **Project number:** 1R01AR080950-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** MARIA TROJANOWSKA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $621,218
- **Award type:** 1
- **Project period:** 2022-07-07 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435724

## Citation

> US National Institutes of Health, RePORTER application 10435724, Lymphatic ERG signaling in scleroderma fibrosis (1R01AR080950-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10435724. Licensed CC0.

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