# Mechanistic and Therapeutic Investigations of Scleroderma

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $360,250

## Abstract

PROJECT SUMMARY
The term scleroderma encompasses a diverse set of conditions that are unified by excessive collagen
deposition in the skin and often internal organs. A common and severe but genetically intractable form
called systemic sclerosis (SSc) shows adult-onset fibrosis in association with autoantibody production.
Recently, we showed that a Mendelian form of scleroderma called stiff skin syndrome (SSS) is caused by
mutations in the integrin-binding domain of fibrillin-1, a matrix protein that also regulates the activity of the
profibrotic cytokine TGF. These mutations impair the ability of cells to make contact with fibrillin-1 via
bridging interactions with integrins. Knock-in mouse models of SSS show fully-penetrant dermal fibrosis and
all of the autoimmune abnormalities characteristic of SSc in association with tissue infiltration of activated
plasmacytoid dendritic cells (pDCs) that are capable of orchestrating immunologic dysregulation and fibrosis
through the production of inflammatory cytokines such as IFN- and IL6. Fibrosis and autoinflammation are
prevented (or even reversed) in SSS mice with interventions that normalize the abnormally high expression
of v3 integrin by pDCs; this complete rescue is phenocopied in SSS mice by blocking cellular signaling
pathways known to influence pDC performance (e.g. TGF and ERK1/2). Notably, fibroblasts derived from
patients with diffuse and active SSc also show concordant phenotypes and therapeutic responses. The
work proposed in this application will fully exploit the first bona fide mouse model of a human presentation
of scleroderma. Aim 1 will interrogate the relative contributions of perturbations in adaptive and innate
immunity by building upon our exciting preliminary data showing full maintenance or complete abrogation of
dermal fibrosis in SSS mice upon introduction of the complete null state for Rag2 (a factor required for the
production of T and B cells) or conditional depletion of pDCs, respectively. We will also explore the
relevance of a potential axis for matrix-initiated pDC activation that has been descriptively implicated in
other autoimmune disorders and is now supported by our preliminary data for SSS. Aim 2 will assess the
therapeutic potential of a pharmacologic antagonist of v3 integrin in scleroderma that is already in clinical
development for cancer. It will also comprehensively scrutinize the role of specific pDC effector functions
including the production of IFN-, IL6, or CXCL4 (a factor that shows excellent temporal correlation with the
onset, severity and progression of SSc). Aim 3 will build upon prior work and our preliminary data showing
that TGF-induced transition of diverse cell types to invasive collagen-producing myofibroblasts is critically
dependent upon Wnt activity and the CAPN9/S2 dimeric calpain complex, respectively. These studies have
the strong potential to unveil novel therapeutic strategies for SSS, SSc and perhaps more common
presentations...

## Key facts

- **NIH application ID:** 9985592
- **Project number:** 5R01AR068379-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Harry C., III Dietz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,250
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985592

## Citation

> US National Institutes of Health, RePORTER application 9985592, Mechanistic and Therapeutic Investigations of Scleroderma (5R01AR068379-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9985592. Licensed CC0.

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