Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated intraocular pressure (IOP) due to insufficient aqueous humor outflow through the trabecular meshwork and Schlemm's canal (SC) is the most important risk factor for glaucoma, a leading cause of blindness worldwide. We previously reported loss of function mutations in the receptor tyrosine kinase TEK or its ligand ANGPT1 cause primary congenital glaucoma in humans and mice due to failure of SC development. Here, we describe a novel approach to enhance canal formation in these animals by deleting a single allele of the gene encoding the phosphatase PTPRB during development. Compared to Tek haploinsufficient mice, which exhibit elevated IOP and loss of retinal ganglion cells, Tek+/-;Ptprb+/- mice have elevated TEK phosphorylation, which allows normal SC development and prevents ocular hypertension and RGC loss. These studies provide evidence that PTPRB is an important regulator of TEK signaling in the aqueous humor outflow pathway and identify a new therapeutic target for treatment of glaucoma.
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PMID:Targeting the vascular-specific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma. 3162 85

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide, and elevated intraocular pressure (IOP) is a major risk factor. While IOP is mainly controlled by adjusting the outflow resistance in the trabecular meshwork (TM), drugs that act directly on the TM are rare. In this study, we discovered a novel compound and pathway that acts on the TM and decreases IOP by genomic, proteomic, and bioinformatic analyses of POAG-derived TMs and experimental validation. Overlapping differentially expressed genes of the TM between patients with POAG and normal controls from two independent gene expression profiles in public databases were analyzed and matched by using the Connectivity Map (CMap). Rottlerin was identified as a potential compound. Subsequent experiments confirmed that rottlerin reversed POAG phenotypes in vitro and that it decreased IOP and actin/extracellular matrix accumulation in vivo with no detectable ocular side effects. SwissTargetPrediction in combination with pathway analysis predicted that the effects of rottlerin may be mediated by activation of the Rap1 pathway. Finally, we confirmed that rottlerin upregulated Rap1 and the downstream PI3K/AKT pathway independent of the MAPK/ERK pathway in a dexamethasone-induced POAG cell model.
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PMID:Rottlerin acts as a therapeutic in primary open-angle glaucoma by targeting the trabecular meshwork via activation of Rap1 signaling. 3236 May 86

Increased stiffness of the Schlemm's canal (SC) endothelium in the aqueous humor outflow pathways has been associated with elevated intraocular pressure (IOP) in glaucoma. Novel treatments that relax this endothelium, such as actin depolymerizers and rho kinase inhibitors, are in development. Unfortunately, these treatments have undesirable off-target effects and a lower than desired potency. To address these issues, a targeted PEG-b-PPS micelle loaded with actin depolymerizer latrunculin A (tLatA-MC) is developed. Targeting of SC cells is achieved by modifying the micelle surface with a high affinity peptide that binds the VEGFR3/FLT4 receptor, a lymphatic lineage marker found to be highly expressed by SC cells relative to other ocular cells. During in vitro optimization, increasing the peptide surface density increased micellar uptake in SC cells while unexpectedly decreasing uptake by human umbilical vein endothelial cells (HUVEC). The functional efficacy of tLatA-MC, as measured by decreased SC cell stiffness compared to non-targeted micelles (ntLatA-MC) or targeted blank micelles (tBL-MC), is verified using atomic force microscopy. tLatA-MC reduced IOP in an in vivo mouse model by 30-50%. The results validate the use of a cell-softening nanotherapy to selectively modulate stiffness of SC cells for therapeutic reduction of IOP and treatment of glaucoma.
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PMID:Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma. 3301 61


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