# Age-Related Meibomian Gland Dysfunction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $562,487

## Abstract

Project Summary/Abstract
The long-term goal of this project is to develop novel approaches to treating meibomian gland
dysfunction (MGD), a major cause of evaporative dry eye disease in the aging population. Meibomian
glands are holocrine glands that are embedded in the tarsal plate of the both the upper and lower eyelid, and
excrete lipid (meibum) onto the surface of the eye to form the lipid layer of the tear film to reduce aqueous tear
evaporation. Dysfunction of the meibomian gland (MGD) identified as atrophy or altered meibum secretion is a
common eyelid disorder having a widespread prevalence of 39-50% in the US population with the incidence
increasing with age that is widely recognized as a major cause of evaporative dry eye disease (EDED). While
patients with EDED and MGD comprise from 37% to 47% of the average Ophthalmologists and Optometrists
practice, management of this disease is primarily palliative due to a lack of knowledge concerning the cellular
and molecular events that cause MGD. To address this UNMET NEED we have evaluated the effects of
conditionally knocking out (CKO) Pparg expression in the meibomian gland using tamoxifen induced
Lrig1Cre/Ppargflox transgenic mice. Our studies show that following 10 weeks of Cre induction there is a male
dominant (3/5 male to 0/35 female) ablation of acini with a shift from meibocyte differentiation to Krt6a+ ductal
differentiation (See Preliminary Studies). These results support our 3D spheroid culture results concerning the
plasticity of meibocyte/ductal epithelial differentiation as well as suggest that there are male/female differences
in the regulation of meibocyte differentiation and renewal by stem/progenitor cells. Together, these findings
suggest the following hypotheses: 1) That direct loss of Pparg signaling leads to an age and sex dependent
loss of meibocyte differentiation, acinar atrophy and dry eye disease; 2) That Pparg signaling transcriptionally
regulates meibocyte differentiation that when lost leads to up-regulation of ductal epithelial differentiation in
progenitor meibocytes; 3) That loss of meibocyte progenitor cells recapitulates loss of Pparg leading to loss of
meibocyte differentiation, acinar atrophy, and dry eye disease. To test these hypotheses, we propose the
following Specific Aims: 1). Determine if loss of Pparg signaling in stem/progenitor meibocytes leads to acinar
atrophy and dry eye by establishing the sex (male/female) and age (1, 3 and 6 months) effects of Ppargflox
knockdown in Sox9-Cre and Lrig1-Cre mice; 2). Identify the Pparg specific transcriptional profile leading to
meibocyte differentiation using scATACseq and ChIP-Seq by comparing wild type to Pparg CKO mice and
identify differences related to meibocyte vs ductal differentiation as well as the effects of age and sex; and 3).
Establish the effects of meibocyte stem/progenitor cell ablation by conditionally knocking out Sox9 and Lrig1
using Krt14-Cre, Sox9flox and Lrig1flox mice and evaluating th...

## Key facts

- **NIH application ID:** 10880106
- **Project number:** 2R01EY021510-09A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** James V Jester
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $562,487
- **Award type:** 2
- **Project period:** 2011-09-30 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880106

## Citation

> US National Institutes of Health, RePORTER application 10880106, Age-Related Meibomian Gland Dysfunction (2R01EY021510-09A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10880106. Licensed CC0.

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