There is substantial evidence that pathological increases in intraocular pressure (IOP) play a causal role in the pathological remodeling of trabecular meshwork cells which regulate the drainage of aqueous humor from the anterior eye however the identity and function of the mechanosensing mechanisms remains largely unknown. The present proposal aims to characterize these mechanisms at biophysical, molecular and cellular levels as well as in bioengineered models of conventional outflow.
Aim 1 will establish the mechanical thresholds of human TM cells obtained from non-symptomatic and glaucomatous patients, characterize effect of mechanical stress (pressure, stretch and swelling) on intrinsic mechanosensitive channels and establish its time- dependent properties (acute & chronic adaptation). This is expected to lead to a novel model of tensile homeostasis in the TM based on balanced activation of opposing types of mechanosensitive channels.
Aim 2 links pressure-sensitive channels to the remodeling of actin cytoskeleton and focal adhesion contacts with the extracellular matrix, uses innovative strain-sensitive optical cytoskeleton probes and defines the function of mechanical coupling in the regulation of the conventional outflow resistance using biomimetic nanoscaffolds populated with healthy and glaucomatous human TM cells. The proposed research thus aims to establish novel conceptual, experimental and translational frameworks that will unify our understanding of retinal IOP regulation within the context of mechanotransduction, cell swelling, volume sensing and calcium homeostasis, with the aim to lead towards the development of effective, first-in-kind treatments for glaucoma.
The pathological response of trabecular meshwork cells to elevated intraocular pressure (IOP) represents a key known risk factor for developing glaucoma yet the identity of the pressure sensing mechanism is unknown, precluding effective treatment. In the present application, we propose to build on recent preliminary accomplishments where we identified a likely mechanotransducer and showed that targeting it lowers IOP in a preclinical glaucoma model. We will characterize its role in pressure sensing and transduction, show how it drives cellular responses that are known markers of glaucomatous TM remodeling, and develop targeting strategies aimed at increasing fluid outflow from the eyes. The results from the project are expect to lead towards novel IOP-lowering strategies that will protecting ocular cells from mechanical stress.
