Congrats Shubham for BrightFocus Grant
Dr. Shubham Maurya was awarded the BrightFocus Foundation National Glaucoma Research award for his proposal titled “Regulation of microglial phenotype by neuroprotective LXB4 in ocular hypertension-induced neuropathy”.
The Project Summery!!
We recently discovered a novel resident neuroprotective retinal astrocytes-RGC lipoxin circuit, which is impaired during retinal stress, including ocular hypertension (OHT) induced glaucoma-like neuropathy. Lipoxins are a family of specialized pro-resolving lipid mediators known to resolve local inflammations. Two endogenous lipoxins endogenously produced by astrocytes directly act on RGCs and are neuroprotective in animal glaucoma models. Lipoxin B4 (LXB4) is the most potent lipoxin in increasing RGCs’ survival and function in a chronic rodent model of OHT. Homeostatic roles and cellular targets of LXB4 in the retina are a critical gap in knowledge. To understand the bioaction of LXB4, retina’s were analyzed by single-cell transcriptomics in LXB4-treated healthy mice. The treatment induced selective changes in gene expression in a limited number of retinal cell types. Unexpectedly, the most significant change in gene expression was observed in microglia. LXB4 treatment downregulated the genes that are part of the microglia ‘sensome’ gene family which maintains homeostasis and regulates microglia phenotype. LXB4-regulated genes drive the switch from a homeostatic to a reactive phenotype. More importantly, the same set of LXB4 downregulated genes were upregulated in a mouse model of chronic OHT along with the markers for microglia activation. Treatment with LXB4 reversed the gene expression toward homeostatic phenotype. These findings are significant as they suggest that LXB4 regulates microglia phenotype by maintaining its homeostatic machinery. We hypothesized that astrocyte-generated LXB4 is a novel checkpoint factor to promote microglial homeostatic function and, thus, is an early protective mechanism against OHT-induced neuropathy. Our research team will test this hypothesis with two specific aims: 1) Characterize time course of microglial activation and regulation by LXB4 treatment in a chronic mouse model of OHT. 2) Investigate the role of the endogenous astrocyte lipoxin pathway as a checkpoint signal for maintaining microglia homeostatic function in OHT. We aim to prove that microglia reactivity and LXB4 regulation of microglia homeostatic functions are key early checkpoints in OHT-induced neuropathy and warrant detailed investigation as treatment targets for glaucoma.
