Identifying and Studying the Molecules Sensing the Pressure in the Eye

Identify potential candidate molecules, called the Piezo channels, sensing elevated intra-ocular pressure (eIOP) in the retina and modify their activity in laboratory models of glaucoma.

Aim 1: Confirm the presence of Piezo channels in the glaucomatous retina. Identification of the type of cells synthesizing Piezo channels in laboratory models of glaucoma and patient eyes. Aim 2: Modulating the activity of the Piezo channels in the retina of laboratory models of glaucoma using specific drugs. Assessing the effect of Piezo channels modulation on retinal cell death and loss of vision. Aim 3: Confirming that Piezo channels mediate the effect of eIOP in the retina. Assessing the effect of the absence of Piezo genes in the retina of laboratory models of glaucoma.

Glaucoma is characterized by the degeneration of the retinal ganglion cells (RGCs) forming the optic nerve and is the leading cause of global irreversible blindness. Elevated intra-ocular pressure (eIOP) is a major risk factor for RGCs degeneration and death but the molecular mechanisms leading to RGCs death are largely unknown. Based on pilot data, we hypothesize that a new set of pressure sensor molecules discovered in 2010 in mammals, the Piezo1 and 2 receptors, expressed by RGCs are sensing IOP. When IOP increases, Piezo 1 and 2 are hyperactivated, leading to high concentration of calcium entering the cells. High concentration of calcium then becomes toxic for cells and they eventually die. In this project, we want to investigate further the role of Piezo1 and 2 receptors in sensing eIOP in an animal model of glaucoma. Using pharmacological and genetic approaches, we will block or ablate the activity of the Piezos in the retina in models of eIOP and measure the proportion of dying RGCs. If the number of dying RGCs decreases in the absence of Piezo1 and 2 activity, this would suggest that they mediate the noxious effect of eIOP on RGCs. This work can pave the way for the design of new therapeutic molecules protecting RGCs from degeneration and death.

Uniqueness:

• Identification of the molecular sensors mediating the effect of eIOP on retinal cell death and loss of vision in laboratory models and human eyes

Innovation:

• The use existing pharmacological and genetic approaches to confirm the role of the molecular sensors in glaucoma will speed up the process of validation.
• Pharmacological approaches may lead to rapid identification and use of existing drugs, specifically modulating the Piezo channels, to reduce eIOP and block retinal cell death.

Biological:

• Our study may advance the general knowledge of the molecular mechanisms sensing IOP in the eye.

Clinical:

• Clinical trials using existing modulators of Piezo channel activity can be performed. Assessing safety and efficacy of these Piezo channels modulators on retinal cell death and loss of vision in patients with glaucoma.