Free the Hippo – to release Glaucoma Pressure

Background

Glaucoma is the leading cause of irreversible blindness worldwide, with an estimated global prevalence of 3.5% among people aged 40–80 years, corresponding to approximately 80 million people and projected to increase to 112 million by 2040 (1,2). Prevalence increases markedly with age, approaching 10% among people aged over 75 (1,2). Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs), ultimately leading to permanent vision loss. Glaucoma is the most common cause of irreversible blindness. Elevated intraocular pressure (IOP) is a key risk factor combined with age, genetic predisposition and immune dysregulation (1,2). Continued fluid production and aqueous humour release via the trabecular meshwork are integral to ocular homeostasis. In glaucoma, pressure builds up because fluid release through the trabecular meshwork is reduced. Increased IOP cause the optic nerve to die. 

Elevated IOP is consequently the principal modifiable risk factor for glaucoma, yet a minor proportion of patients develop glaucomatous neurodegeneration at IOP within normal range. Conversely, some individuals with ocular hypertension do not develop glaucoma, indicating marked inter-individual variation in cellular susceptibility to pressure, with early indications that metabolic/lipidomic pathways contribute to differences in glaucoma susceptibility. However, the mechanisms of the underlying pressure sensing are unclear, and likewise the heterogeneity of divergent IOP across the patient population is currently unknown.

This phenotype switching in glaucoma represents a key translational knowledge gap.

Therapeutically modulating altered tissue mechanics could directly reveal new neuroprotective strategies that preserve RGCs and slow vision loss. We recently identified that the cellular Hippo pathway mediates the cellular response to fluid pressures (3), and using an isogenic cellular model and high-content imaging, evaluated multiple drugs targeting this pathway (4). Our unique experimental setup, combining microfluidics and quantitative phase imaging, allows us to analyse cellular responses to fluid pressure and explore how targeting mechanotransductive responses might reduce ocular pressure. 

This project will evaluate the cellular responses across patients and seek to resensitise cells to release IOP. 

Free the Hippo – to release Glaucoma Pressure

We hypothesis that evaluating cellular responses to varying IOPs enables prediction of glaucoma patient outlook. We anticipate that either modulating IOP dynamics, or the trabecular meshwork cellular response to IOP, enables therapeutical modulation toward a neuroprotective phenotype. If successful, our approach will reverse pressure buildup, reduce neuroinflammation and protect RGCs, and the project thereby aims to change clinical practice longer-term.

Aim 1: Biophysical profile glaucoma patient cellular responses to IOP.

Aim 2: Determine IOP mediated cellular responses.

Aim 3: Test targeted modulation to promote pressure release.

This project seeks to define the heterogeneity in cellular responses to pressure, a key modifiable risk factor in glaucoma. Additionally, it seeks to identify the molecular signatures of pressure susceptibility and how resilience might reveal biologically distinct glaucoma subgroups, providing a mechanistic basis for future patient stratification, risk prediction and development of more targeted therapeutic approaches. 

The PhD candidate is consequently uniquely positioned to deliver this timely and clinically potentially transformative project.

Training: The candidate will be provided interdisciplinary and professional training, that ensures the candidate becomes and agile T-shaped researcher leader with diverse advanced skillsets, including in Microfluidics and quantitative-phase-imaging, FLIM and High-content imaging; Quantitative analysis; Bioengineering; Proteomics, Transcriptomics and lipodomics, Multiparametric bioinformatic analyses; Biochemical analysis andPrimary cell development. PPIE activities will be integrated throughout to strengthen PhD candidate development and increase dissemination, real-world visibility and impact. The project will be integrated within the IRR based multidisciplinary Robert O Curle Eyelab and eye pavilion communities and take advantage of our recently developed capacity enabling label free analysis to diverse fluid pressures at the single cell resolution. Complimentary unique expertise and training is provided at Karolinska. 

References: 

1): Wang Z et al., Global Glaucoma Prevalence: Burden and Projection to 2060. Am J Ophthalmol, 2026 Mar:283:324-335. 

2): Jayaram H, Kolko M, Friedman DS, Gazzard G. Glaucoma: now and beyond. The Lancet. 2023;402:1788–1801. 

3): Park J*, Jia S*, Salter D, Bagnaninchi P and Hansen CG. The Hippo pathway drives the cellular response to hydrostatic pressure, EMBO J (2022), 41:e108719. 

4): Cunningham R, Jia S, Purohit K, Fairley M, Maniak MK, Lin Y, Hui NS, Graham R, Rossi A, Cholewa-Waclaw J, Bagnaninchi PO, N Carragher and Hansen CG. Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma. Life Science Alliance, 2025.