# Defining mechanisms driving dry eye disease progression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $104,973

## Abstract

PROJECT SUMMARY (Revised July 15, 2021) – NO CHANGES FROM PARENT GRANT
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 dry eye disease, pathological alterations in the cornea are among the most
common and debilitating clinical manifestations of autoimmune-mediated dry eye. 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 at late disease stages that may underlie disease 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 cells in the homeostatic cornea. We will
then seek to elucidate the impact of dry eye on the identity of the corneal cell lineages at late stage disease.
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:** 11046163
- **Project number:** 3R01EY033040-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sarah Monica Knox
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $104,973
- **Award type:** 3
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11046163

## Citation

> US National Institutes of Health, RePORTER application 11046163, Defining mechanisms driving dry eye disease progression (3R01EY033040-04S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11046163. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*