# Defining mechanisms driving dry eye disease progression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $397,701

## Abstract

PROJECT SUMMARY
Aqueous-deficient dry eye is among the most common and debilitating clinical manifestations of systemic
autoimmune diseases such as Sjögren's, lupus and rheumatoid arthritis. While it is well established that
chronic inflammation of the ocular surface and exocrine glands (e.g., lacrimal gland) represents the
predominant driving force in autoimmune-mediated dry eye disease, pathological alterations in the cornea are
among the most common and debilitating clinical manifestations. With the cornea providing approximately two-
thirds of the eye's focusing power and protecting the anterior eye from environmental, inflammatory and
microbial insult, disease-mediated corruption of tissue function and homeostasis has a vast array of
pathological outcomes. Indeed, a multitude of studies in both human patients and mouse models of aqueous-
deficient dry eye illustrate late stage disease encompasses epithelial barrier disruption, epithelial hyperplasia,
reduced corneal innervation and inflammatory cell infiltration. Thus, dry eye disease induces pathological
changes along multiple levels. However, due to the limited understanding of the cellular makeup of the cornea,
including the lineage relationships of specific cell types, the impact of dry eye on cell heterogeneity and lineage
outcomes is unknown. To help solve this significant problem, we have begun to define the cellular diversity and
differentiation trajectories of corneal cells and how these are perturbed by dry eye disease using single cell
nuclei RNAsequencing in combination with the autoimmune regulatory (Aire)-deficient mouse model. Using this
model, we have also begun to identify novel changes in corneal cell composition during the emergence of dry
eye that may underlie disease development and progression. Based on these data we hypothesize that
disease progression is promoted by an alteration in corneal cell fate that compromises the repair and cellular
replenishment of the tissue. We propose to explore this hypothesis by first defining epithelial and stromal cell
heterogeneity, differentiation trajectories and stem/progenitor cells in the homeostatic cornea. We will then
seek to elucidate the mechanisms by which dry eye disease development impacts the self-renewal,
differentiation capacity and function of corneal cells during dry eye disease development. Outcomes from these
studies will aid in the development of therapeutics to halt disease progression, as well as the generation of
diagnostic targets for early intervention.

## Key facts

- **NIH application ID:** 10458017
- **Project number:** 5R01EY033040-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sarah Monica Knox
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,701
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458017

## Citation

> US National Institutes of Health, RePORTER application 10458017, Defining mechanisms driving dry eye disease progression (5R01EY033040-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10458017. Licensed CC0.

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