# Transcriptional control of lipid biogenesis in trabecular meshwork and intraocular pressure regulation

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $486,865

## Abstract

Project Summary:
 Glaucoma is a disease of the optic nerve causing irreversible blindness and important public health
concern with around 76.9 million glaucoma patients, which is set to increase to 111.8 million in 2040.
Primary open-angle glaucoma (POAG) is a form of glaucoma characterized by elevated intraocular
pressure (IOP). A rise in IOP above normal is a major risk for glaucoma with significant consequences
on vision and quality of life. Lowering IOP by 20% significantly decreases the risk of developing
glaucoma in patients with elevated IOP. High IOP in the eye is due to the decreased removal of aqueous
humor through the trabecular meshwork (TM). Changes in the lipid composition of the TM can modify
the actin cytoskeleton interactions can with extracellular structural and biochemical support called the
extracellular matrix (ECM) in the drainage pathway. This process can increase the stiffness of the
drainage pathway tissue attributing to an increase in the IOP. However, the contributions of TM lipids
to stiffness as well as the process of reversing this stiffness have not yet been understood. This is due to
the lack of information on the control of lipid signaling events leading to altered stiffness. In our
serendipitous and novel observation, we have identified that a transcriptional factor called sterol
regulatory element binding protein (SREBP) is activated under constant mechanical stretch and
elevated pressure. Inactivating SREBP lowers the actin tension, ECM deposition, enzymes involved in
lipid biosynthesis, and most significantly lowers IOP. However, this leaves us with many unanswered
questions on how SREBP integrates the biophysical and biochemical entities including TM lipids,
membrane tension, actin cytoskeleton, ECM, and TM stiffness to modulate IOP. Towards this, we aim
to test the hypothesis that – 1. transcriptional control of lipogenesis by SREBP in the TM
outflow pathway is a critical regulator of IOP by A. assessing the correlation between SREBP
activation on IOP changes, B. characterizing the SREBP-dependent temporal changes in lipogenic
genes and enzymes and the ECM distribution in the TM outflow pathway and C. evaluating the role of
IOP in activation of SREBPs, and 2. SREBP activation regulates TM tissue biomechanics by
changing the TM cholesterol and phospholipid contents by A. identifying the contributions of
major lipogenic rate-limiting enzymes like acetyl CoA carboxylase (ACC) for fatty acid biosynthesis and
HMGCoA reductase (HMGCR) for cholesterol biogenesis on ECM remodeling, B. investigating the real-
time changes in TM membrane tension, actin and microtubule architecture, and C. defining the
cooperative signals between ECM and cellular lipids on the contractile forces generated by the TM
under conditions of tuned SREBP activation. Together, this work will uncover the new biology of lipids
in TM to modulate IOP and identify novel targets to reduce the disease burden of elevated IOP.

## Key facts

- **NIH application ID:** 10882378
- **Project number:** 1R01EY035412-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Padmanabhan Paranji Pattabiraman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $486,865
- **Award type:** 1
- **Project period:** 2024-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882378

## Citation

> US National Institutes of Health, RePORTER application 10882378, Transcriptional control of lipid biogenesis in trabecular meshwork and intraocular pressure regulation (1R01EY035412-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882378. Licensed CC0.

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