Lens Physiology and Optics Group

Prof. Paul Donaldson

Research projects in my group are focused on determining how the interaction of a variety of ion channels and transporters contribute to the establishment and maintenance of the transparent and refractive properties of the lens. We have shown that spatial differences in ion channels and transporters drive an internal microcirculation of ions, water, and solutes that delivers nutrients to the lens core, controls lens volume and actively maintains the optical properties of the lens. The outflow of water through gap junction channels has been shown to generate a substantial hydrostatic pressure gradient that is maintained relatively constant by a dual feedback system in which changes in pressure are sensed by mechanosensitive TRPV1/4 channels. By studying how the different components of this system are regulated in the normal lens and how their functions are disrupted with age, we are attempting to identify drug targets against which novel therapies designed to delay the onset and progression of presbyopia and cataract can be developed. To achieve this, we are pursuing a number of projects in animal models which are then translated into humans.

Current Research Projects

Characterisation of the pathways that regulate the lens water transport via the microcirculation system

Dr Yadi Chen, Dr Roscia Petrova (Research Fellows), Yosuke Nakazawa (Keio University Japan)

Pharmacological activation of mechanosensitive TRPV1 and TRPV4 channels, changes in extracellular osmolarity, and alterations in zonular tension can all modulate water transport in the lens. In this project, we are characterising how these different stimuli interact to set and maintain water transport. To achieve this, we are combining pressure measurements of water transport with confocal based functional imaging of intracellular signalling pathways in order to determine how these different stimuli converge on the TRPV1/4 dual feedback pathway to regulate lens water transport with the view to identify reagents that can pharmacologically regulate water transport and therefore overall lens optics.

Characterisation of the effect of altering lens water transport/pressure regulation on the biomechanical properties of the lens of the normal and presbyopic lens.

Dr Yadi Chen, Dr Peter Qiu (Research Fellows), A/P Ehsan Vaghefi (Associate Professor) and Bianca Heilman (University of Miami)

The onset of presbyopia in the lens is associated with an increase in tissue stiffness. To test the relationship between lens water transport/pressure and tissue stiffness regional changes to lens stiffness will be measured using a spin test apparatus which captures images of lenses before, during and after a lens spinning protocol to determine the amount of lens deformation induced by the spinning protocol. A deformation profile is then reconstructed using an axisymmetric model that calculates the shear modulus in different regions of the lens. In addition, in collaboration with the University of Miami an Ex Vivo Accommodation Simulator II (EVAS II) will be used to simultaneously stretch and image the change in shape of the lens using optical coherence tomography (OCT). By performing these experiments in solutions formulated to modulate lens water transport, we will establish whether alterations to water content and transport (pressure), result in an increase in the stiffness of the lens nucleus and a reduction in accommodation amplitude. Furthermore, these systems will enable us to test whether regulators of lens water content and transport identified by the MVRC as potential therapies to treat presbyopia.

Use of Magnetic Resonance Imaging (MRI) to study water content and transport in animal models and humans in vivo.

Dr Alyssa Lie, Dr Wilson Pan, Dr Peter Qiu (Research Fellows), A/P Ehsan Vaghefi (Associate Professor), Tom White (SUNY Stony Brook, USA)

We have optimized an in vivo MRI-based optical modelling platform that can be applied to study water transport in both transgenic mice models and in humans. Working with our collaborator in Stony Brook, we are applying our protocols to transgenic mouse models, in which key components of the microcirculation system have been genetically manipulated, to determine how different ion channels and transporters contribute to water transport and the maintenance of the optical properties of the lens. In humans, we are using our platform to investigate whether changes in water transport accompany the onset of cataract formation by studying patients who have under gone an operation to remove the vitreous. Since the majority of post-vitrectomy patients develop nuclear cataracts within two years, studying changes in water transport that precede cataract formation in vitrectomy patients will allow longitudinal studies to be conducted over a condensed time period and will facilitate the testing of our hypothesis that failed water transport is one initiating cause of post-vitrectomy nuclear cataract. In addition, our in vivo MRI-based optical modelling platform is being used to test the hypothesis that changes in lens water content/transport are relevant to human accommodation. These experiments involve using MRI to monitor lens geometry and spatially map the free and total water content in pre-presbyopic and presbyopic cohorts of volunteer human subjects who are presented with stimuli-to-accommodation (STA) to induce accommodation. Changes in lens shape and free/total water content across STA are assessed and compared between pre-presbyopic and presbyopic cohorts. These experiments will allow us to determine if changes in lens water content contribute to the process of accommodation, and whether changes in free water initiates the onset of presbyopia.