Optic nerve head metabolic change promotes fibrosis

Abstract Extracellular matrix changes, metabolic reprogramming, glial hypertrophy, axon transport deficit, and inflammation contribute to retinal ganglion cell (RGC) axon loss at the optic nerve head in glaucoma. Fibrosis at the optic nerve head develops in response to the strain that is the result of increased intraocular pressure

observed in primary open angle glaucoma patients. However, the fibrosis becomes maladaptive as it impinges upon the RGC axons that traverse the optic nerve head. Signaling pathways that regulate fibrosis intersect with, and promote, specific metabolic pathways which in turn, modify the cytoskeleton and the extracellular

matrix. Therefore, a critical question is to what degree metabolic pathways dictate fibrotic changes in the optic nerve head, and whether these pathways can be modified to resolve pathological fibrosis. The long-term goal of this work is to understand how metabolism and fibrosis intersect so that we may

promote survival of retinal ganglion cell axon structure and function in the optic nerve head. Our central hypothesis is that glaucoma-associated extracellular matrix changes drive metabolism in optic nerve head cells to promote continued fibrotic response. This hypothesis has emerged from our analysis of metabolic

change in optic nerve head astrocytes under glaucoma-associated stress, including indications that these cells prioritize glutaminolysis, a key promoter of collagen synthesis. YAP/TAZ, two transcriptional co-activators that are the final effectors for ECM-to-integrin signaling and have been implicated in glaucoma-associated fibrosis,

regulate the enzymes critical for glutaminolysis. Thus, promotion of a particular metabolic path is the result of cellular mechanosensing in astrocytes, and allows those cells to continue to support the fibrotic response. Resisting the raised intraocular pressure present at the optic nerve head as in glaucoma is the basis of the

fibrotic response, but the fibrosis eventually becomes a maladaptive positive feedback loop. Metabolic reprogramming enables this positive feedback loop, so it is worth testing whether manipulating metabolism in astrocytes and lamina cribrosa cells can limit the maladaptive response. We will test our hypothesis by 1) establishing that glutaminolysis in astrocytes and lamina cribrosa (LC)

cells of the optic nerve head is the result of YAP/TAZ transcriptional coactivation via extracellular matrix signaling. We anticipate learning that astrocytes and LC cells prioritize glutaminolysis through YAP/TAZ signaling to generate amino acids to be used for collagen synthesis. Secondly, we will interfere with

glutaminolysis in astrocyte and LC cells to test the suspected positive-feedback metabolic link to fibrosis. We intend to show that metabolic pathways other than breakdown of glutamine will not facilitate the fibrotic response of astrocytes and LC cells under glaucoma-associated strain. Establishing the necessity of specific

metabolic change to the fibrosis response of astrocytes and LC cells in the glaucomatous optic nerve head will reveal a means by which fibrosis can be targeted to maintain retinal ganglion cell axon function and survival.