Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ocular pathologic angiogenesis is a causative factor for retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. In the present study, we examined the effects of rapamycin and everolimus, inhibitors of mammalian target of rapamycin (mTOR), on retinal pathologic angiogenesis in mice with oxygen-induced retinopathy (OIR), an animal model of proliferative ischemic retinopathy. Mice were exposed to 80% oxygen from postnatal day (P) 7 to P10, and were then brought into room air and subcutaneously injected with rapamycin and everolimus. The neovascular tufts, the size of the central avascular zone, and the immunoreactivity for phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTOR activity, were evaluated in flat-mounted retinas. Retinal neovascular tufts and vascular growth in the avascular zone were observed in P15 mice with OIR. In addition, intense immunoreactivity for pS6 was detected in the neovascular tufts and in endothelial cells located at the vascular-avascular border. Both rapamycin and everolimus reduced the extent of retinal neovascular tufts and pS6 immunoreactivity, but they also increased the size of the avascular zone. Thus, activation of the mTOR pathway in endothelial cells contributes to retinal pathologic angiogenesis, and mTOR inhibitors that target proliferating endothelial cells are promising candidates as anti-angiogenic agents for the treatment of vasoproliferative retinal diseases.
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PMID:Anti-angiogenic effects of mammalian target of rapamycin inhibitors in a mouse model of oxygen-induced retinopathy. 2536 88

Retinopathy of prematurity (ROP) is characterized by late-phase pathologic retinal vasoproliferation. Gremlin is a novel vascular endothelial growth factors (VEGF) receptor 2 (VEGFR2) agonist and promotes angiogenic response. We demonstrated that gremlin expression was significantly increased in retinas of ROP model mice, which was correlated with VEGF upregulation. In retinal pigmentation epithelial (RPE) cells, gremlin activated VEGFR2-Akt-mTORC2 (mammalian target of rapamycin complex 2) signaling, and promoted cell proliferation, migration and VEGF production. VEGFR inhibition (by SU5416) or shRNA knockdown almost abolished gremlin-mediated pleiotropic functions in RPE cells. Further, pharmacological inhibition of Akt-mTOR, or shRNA knockdown of key mTORC2 component (Rictor or Sin1) also attenuated gremlin-exerted activities in RPE cells. We conclude that gremlin promotes RPE cell proliferation, migration and VEGF production possibly via activating VEGFR2-Akt-mTORC2 signaling. Gremlin could be a novel therapeutic target of ROP or other retinal vasoproliferation diseases.
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PMID:Gremlin promotes retinal pigmentation epithelial (RPE) cell proliferation, migration and VEGF production via activating VEGFR2-Akt-mTORC2 signaling. 2789 90

Pathological ocular angiogenesis is a causative factor of retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. Vascular endothelial growth factor (VEGF) plays an important role in pathological angiogenesis, and anti-VEGF agents have been used to treat the ocular diseases that are driven by pathological angiogenesis. However, adverse effects associated with the blockade of VEGF signaling, including impairments of normal retinal vascular growth and retinal function, were suggested. Therefore, the development of a safe, effective strategy to prevent pathological ocular angiogenesis is needed. Recent studies have demonstrated that inhibitors of the mammalian target of rapamycin (mTOR) target proliferating endothelial cells within the retinal vasculature. Here, we review the potential of targeting the mTOR pathway to treat pathological ocular angiogenesis.
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PMID:Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis. 2919 29