[R01] Ferrochelatase as a mediator of ocular angiogenesis
Ente: National Eye Institute
Scadenza: 2028-03-31
Importo max: 305.695 EUR
Paese: US
Descrizione
The neovascular eye diseases retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular
age-related macular degeneration are major causes of blindness through the lifespan. Not all patients respond
to existing therapies, so there is thus a critical need to find novel cellular components that could be targeted to
block the pathological angiogenesis that is characteristic of these diseases. Ferrochelatase (FECH) is one
such component, necessary for proliferation of endothelial cells in vitro and in vivo. FECH is responsible for
inserting ferrous ion into protoporphyrin IX, the final step in heme biosynthesis. The previous grant period
yielded findings that FECH is upregulated in murine and human choroidal and retinal neovascularization, that
FECH inhibition leads to depletion of hemoproteins in endothelial cells, and that FECH loss blocks heme-
dependent oxidative phosphorylation in endothelial cells. Reduced FECH activity also surprisingly blocks
glycolysis. In addition, the first drug-like FECH inhibitor, SH-17023 was developed and shown to be
antiangiogenic in vitro and in vivo. Building on this work, the current goal is to define the mechanism of how
heme synthesis through FECH and glycolysis impacts endothelial cell biology and neovascularization. The
rationale for this research is that FECH is a significant mediator of angiogenesis, a potential therapeutic target,
and a previously unappreciated regulator of the expression and function of glycolytic enzymes. The overall
hypothesis is that FECH, via controlling heme availability, is an integrated master regulator of multiple
proangiogenic pathways, including glycolysis. Guided by strong preliminary data, the hypothesis will be tested
via two specific aims: 1. Delineate the mechanism of FECH’s influence on glycolysis and angiogenesis. The
glycolysis enzymes dysregulated by heme synthesis inhibition in endothelial cells and their heme-dependent
transcriptional regulation will be assessed in endothelial cells. Glycolytic function and related metabolic
pathways will be assessed by Seahorse, targeted metabolomics, and stable isotope tracing. The influence of
this heme-dependent glycolysis regulation on endothelial cell function will be determined, along with the cell-
type specificity of this effect. 2. Evaluate the first drug-like small molecule FECH inhibitor in ocular
neovascularization. The pharmacokinetics and toxicity of SH-17023 will be quantified. Then, this novel
molecule will be tested for efficacy in the oxygen-induced retinopathy, Vldlr-/-, and JR5558 retinal, subretinal,
and choroidal neovascularization models, plus synergy with anti-VEGF therapy. Overall, this work is
innovative, as it is the first mechanistic study of the links between heme synthesis, glycolysis, and posterior
ocular angiogenesis, and the first characterization of direct FECH inhibition with a drug-like small molecule for
retinal and choroidal neovascularization. The work is highly significant bec
Istituzione: UNIVERSITY OF TORONTO
PI: Timothy W Corson
Progetto: 5R01EY025641-09
Settori: National Eye Institute
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