Cellular and Molecular Mechanisms that Contribute to Pressure-Induced Retinal Inflammation and Pathology

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: DAVID  KRIZAJ
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $381,250
Funding agency: National Eye Institute

PROJECT SUMMARY/ABSTRACT
Mechanosensitive ion channels were shown to drive mechanically induced inflammatory signaling in the central
and peripheral nervous systems and to exacerbate pathology in neuropathies, skeletal diseases, traumatic brain
injury and other neurodegenerative conditions. Suppressing their activation with gene knockdown and
pharmacology reduces inflammatory neuropathy and neuronal injury yet despite this knowledge their role in
neuroinflammation is little understood, and their contribution to pressure-associated retinal diseases such as
glaucoma has never been investigated. The goal of the proposed project is to resolve this major gap in
knowledge by defining the molecular targets of intraocular pressure in the principal retinal macroglia, the Müller
cell, and establish the significance of Müller pressure sensing for neuroinflammation, glia-neuronal interactions
and neurodegeneration.
The overall hypothesis of this project is that mechanosensitive TRP and piezo channels trigger and drive
inflammatory activation in the presence of mechanical stressors such as intraocular pressure and strain and that
this process can be targeted by pharmacological/genetic methods to alleviate neuronal injury. We will address
this hypothesis in two specific aims. Aim 1 focuses on the characterization of properties of mechanoactivated
ion channels that mediate pressure signaling in Müller cells. In Aim 2 we propose to take advantage of new
conditional mouse models to elucidate how pressure elevations induce reactive gliosis, the role of
mechanotransduction in glia-glia and glia-neuronal circuits, and significance of this mechanism for ganglion cell
stress and survival. Successful completion of these multidisciplinary, thematically related yet independent
approaches may help define new diagnostic and treatment strategies in hypertensive glaucoma.

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