Project Details
Description
PROJECT SUMMARY
Subretinal fibrosis is an end-stage fibrous plaque/disciform scar that progresses from choroidal
neovascularization (CNV) of neovascular age-related macular degeneration (nAMD). Subretinal fibrosis
compromises highly organized anatomical layers and tightly coordinated cellular interactions, inevitably leading
to irreversible visual impairment. Current treatment for subretinal fibrosis is limited and thus, therapeutic
strategies for the inhibition of subretinal fibrosis are imperative.
Multiple cell types, including endothelial cells (ECs), retinal pigment epithelium (RPE) cells, macrophages
and glial cells, contribute to subretinal fibrosis by either differentiating into mesenchymal-like cells and further
differentiating into α-smooth muscle actin-positive myofibroblasts and/or producing profibrotic and
proinflammatory factors. However, the underlying metabolic mechanisms for these cellular and molecular
activities remain poorly defined. Glycolysis is a metabolic pathway utilized by many proliferative cells. Our
preliminary data show that cells in subretinal fibrotic areas are hyper-glycolytic, as evidenced by high levels of
glycolytic enzymes and glycolytic regulators/activators including 6-phosphofructo-2-kinase/fructose-2, 6-
bisphosphatase isoform 3 (Pfkfb3), a critical enzyme for activation of glycolysis in various highly proliferative
cells. Pfkfb3 catalyzes the synthesis of fructose-2,6-bisphosphate (F2, 6P2), which is the most potent allosteric
activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme for glycolysis. We have demonstrated that
high levels of glycolytic enzymes including Pfkfb3 are present in the RPE/choroid complex isolated from laser-
induced and spontaneous subretinal fibrosis in C57BL/6j mice and very low–density lipoprotein receptor deficient
(Vldlr-/-) mice and that the area of subretinal fibrosis is markedly decreased in Pfkfb3-/+ mice. Our in vitro studies
have also shown that PFKFB3/Pfkfb3 deletion in RPE cells and macrophages inhibits their transition to
mesenchymal or myofibroblast cells as well as reducing their production of proinflammatory and profibrotic
factors. We hypothesize that Pfkfb3-mediated glycolysis in macrophages and RPE cells induces their transition
to mesenchymal cells and/or myofibroblasts and induces their production of profibrotic and proinflammatory
factors by activating HIFs pathways, eventually leading to the development of subretinal fibrosis. To test our
hypothesis, we have generated a variety of genetic mice and established mouse subretinal fibrosis models with
laser-induced CNV and spontaneous CNV in Vldlr-/- mice. We will investigate the effect on subretinal fibrosis of
Pfkfb3 deficiency or inhibition in myeloid and RPE cells using specific genetic and pharmacological tools with an
integrated approach of in vivo and in vitro models. Our study will define the role of PFKFB3-mediated metabolism
in the development of subretinal fibrosis and validate PFKFB3 inhibition as a novel strategy for the treatment of
subretinal fibrosis.
Status | Not started |
---|
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.