# Molecular regulation of fibroblast activation in Thyroid Eye Disease

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $373,450

## Abstract

Thyroid eye disease (TED), also referred to as thyroid-associated orbitopathy or ophthalmopathy is the most
common orbital pathology. TED is an autoimmune disease that occurs in up to half of patients with Graves’
disease. In TED, the tissues surrounding the eye become inflamed and ultimately remodel to cause protrusion
of the eyes, swelling around the eyes, alteration of lid position, and double vision. In the most advanced cases,
the expanded tissues compress the optic nerve, causing vision impairment. These clinical manifestations of TED
reflect tissue changes triggered by autoantibodies that activate orbital fibroblasts that stimulate proliferation of
lipid-laden adipocytes and scar-forming myofibroblasts. Orbital fibroblasts also produce excessive amounts of
extracellular matrix composed of hyaluronan and collagen, which further increases the size and stiffness of
orbital tissue. There is presently no cure for TED; corticosteroids, radiation therapy, and surgery are routinely
used to manage TED symptoms and signs. Teprotumumab, an insulin-like growth factor 1 receptor (IGF1R)
blocking antibody has emerged as the first disease-specific treatment for TED. However, a critical knowledge
gap that limits our understanding of TED is how autoantibodies activate IGF1R signaling in orbital fibroblasts to
promote eye disease. IGF1R can stimulate proliferation and increase myofibroblast formation. The predominant
antigen in TED is the thyroid stimulating hormone receptor (TSHR). How IGF1R interacts with TSHR and TED
autoantibodies in the disease is a fundamental and unresolved question. One potential mechanism is through
the aryl hydrocarbon receptor (AHR). The AHR is a ligand-activated transcription factor that binds synthetic and
naturally derived aromatic hydrocarbons. The AHR controls aspects of cell growth, development and the immune
system. Evidence suggests that AHR blocks TSHR and IGF1R signaling in vivo and in vitro. However, the
mechanism(s) are unclear and whether the AHR regulates these pathways in TED is unknown. One of the most
significant risk factors for developing TED is smoking. Smoking activates a transcription factor called hypoxia
inducible factor 1 alpha (HIF1a). AHR and HIF1a compete to control cell fate. Smoking may disrupt the HIF1a-
AHR balance thereby further increasing IGF1R/TSHR signaling. Central Hypotheses: The AHR blocks
IGF1R/TSHR signaling, and loss of this interaction is a primary event in the pathophysiology of TED. Aim
1: Define the molecular pathway(s) by which the AHR blocks orbital fibroblast activation. Aim 2: Determine the
role of cigarette smoke exposure in promoting HIF1a and IGF1R signaling while blocking AHR in orbital
fibroblasts. Aim 3: Evaluate the ability of the AHR ligands to block TED autoantibody driven TSHR/IGF1R
signaling. Impact: Our findings will show that AHR blocks TSHR and IGF1R signaling in TED. Accomplishing
the specific aims will establish a molecular mechanism whereby smoking exacerbates IG...

## Key facts

- **NIH application ID:** 10475581
- **Project number:** 5R01EY031398-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Collynn Fremont Woeller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $373,450
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475581

## Citation

> US National Institutes of Health, RePORTER application 10475581, Molecular regulation of fibroblast activation in Thyroid Eye Disease (5R01EY031398-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475581. Licensed CC0.

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