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Karsten Gronert, PhD

Karsten Gronert, PhD

University of California, Berkeley
The Dr. Henry A. Sutro Family Grant for Research
Project: LXB4 Regulation of Microglia Homeostatic Function a Neuroprotective Target
Project Summary:

Lipoxins and their receptors are a recently identified resident neuroprotective circuit in the retina. Our current understanding places astrocytes as the source of lipoxins and retinal ganglion cell as their only known target. Retinal stress and ocular hypertension downregulate the homeostatic formation of lipoxin and treatment with Lipoxin B4 (LXB4) is neuroprotective in a model of glaucoma. The mechanism of action for LXB4 and additional cellular targets in the retina remain to be discovered. Single cell RNA and kinase screening assays identified potent and cell selective actions for LXB4 in healthy retinas. Unexpectedly, the cell type targeted by LXB4 treatment in healthy retinas were microglia, the resident immune cell in the retina and optic nerve. LXB4 down-regulated genes that are upregulated by ocular hypertension. These genes control microglial reactivity, which switches their function from homeostasis to driving inflammation and injury responses. LXB4 treatment reduced microglia reactivity in a model of chronic ocular hypertension. Reactive microglia are a key feature of retinopathy and neurodegenerative diseases such as Alzheimer’s. Hence, LXB4 regulation of microglia may be an important early checkpoint to maintain their homeostatic function. This project aims to establish when retinal and optic nerve microglia switch to a reactive phenotype in glaucoma pathogenesis and how they are regulated by astrocyte-generated lipoxins and LXB4 treatment. The goal is to establish proof of concept that regulation microglia homeostatic function is a novel mechanism for the neuroprotective actions of LXB4 and a potential therapeutic target.