Endothelial Tyrosine Kinase Tie1 Is Required for Normal Schlemm’s Canal Development

2022 ◽  
Author(s):  
Jing Du ◽  
Benjamin R. Thomson ◽  
Tuncer Onay ◽  
Susan E. Quaggin
Keyword(s):  
Intraocular Pressure ◽  
Quantitative Polymerase Chain Reaction ◽  
Schlemm’S Canal ◽  
Knock Out ◽  
Schlemm's Canal ◽  
Elevated Intraocular Pressure ◽  
Knock Out Mice ◽  
And Function ◽  
The Impact

Background: Schlemm’s canal (SC) is a large vessel residing in the iridocorneal angle and is required to regulate aqueous humor outflow. Normal SC structure and function is indispensable for maintaining normal intraocular pressure, and elevated intraocular pressure is a risk factor for development of glaucoma. Recent reports have identified a key role of the angiopoietin-Tie2 pathway for SC development and function; however, the role of the orphan receptor Tie1 has not been clarified. Methods: We used Tie1 knock out mice to study the function of Tie1 in SC development and function. Real-time quantitative polymerase chain reaction and Western blot analyses were used to verify Tie1 deletion. High-resolution microscopy of mouse SC whole mount and cross sections were used to study SC morphology. Measurement of intraocular pressure in live mice was used to study the impact of Tie1 on SC function. Results: Tie1 is highly expressed in both human and mouse SC. Tie1 knock out mice display hypomorphic SC and elevated intraocular pressure as a result of attenuated SC development. Conclusions: Tie1 is indispensable for SC development and function, supporting it as a novel target for future SC-targeted glaucoma therapies and a candidate gene for glaucoma in humans.

Trabecular Bypass: Effect of Schlemm’s Canal and Collector Channel Dilation

2004 ◽  
Author(s):  
Jianbo Zhou ◽  
Gregory T. Smedley
Keyword(s):  
Intraocular Pressure ◽  
Second Order ◽  
Polynomial Equations ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Elevated Intraocular Pressure ◽  
Order Polynomial ◽  
Trabecular Bypass

An ocular outflow model is proposed to theorize the effect of Schlemm’s canal (SC) and/or collector channel (CC) dilation combined with a trabecular bypass on elevated intraocular pressure (IOP) in glaucomatous eyes. The dilated height of the elliptic SC is largest at the bypass and linearly deceases to the non-dilated height over the dilated circumferential length. The CC dilation is modeled with a reduced outflow resistance of second order polynomial. Equations governing the pressure and flow in SC are solved numerically. The model predicts that the IOP is reduced substantially with moderate dilation from the normal 20 μm to 40 μm at the bypass. SC dilation is more effective for eyes with smaller SC. The dilation of CC can also significantly lower the IOP. With the trabecular bypass alone, the elevated IOP is expected to drop to the mid-to-high teens. The IOP can be further reduced by another 3 to 6 mmHg with moderate SC and CC dilation.

scholarly journals Suture Distension of Schlemm’s Canal in Canaloplasty: An Anterior Segment Imaging Study

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Livia M. Brandao ◽  
Andreas Schötzau ◽  
Matthias C. Grieshaber
Keyword(s):  
Intraocular Pressure ◽  
Anterior Segment ◽  
Imaging Study ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Anterior Segment Imaging ◽  
The Difference ◽  
Cup To Disc Ratio

Purpose. The object of this study was to investigate the role of the suture stent regarding its impact on reduction of intraocular pressure (IOP) in canaloplasty based on the distension of the inner wall of Schlemm’s canal.Methods. Nineteen glaucoma patients who underwent canaloplasty with successful positioning of the tensioning suture were included. The measurements were analyzed using linear mixed models, with the means adjusted to IOP, age, cup-to-disc ratio, and time of follow-up.Results. Mean follow-up time was 27.6 months (SD 10.5). Mean intraocular pressure (IOP) was 24.6 mmHg (SD 5.29), 13.8 (SD 2.65), and 14.5 (SD 0.71) before surgery, at 12 months, and at 36 months after surgery, respectively. 57.9% of patients had no medication at last evaluation. Differences and variations of measurements between the devices over a time of 12 months were not significant (p= 0.15 to 0.98). Some angles of distension associated with the suture stent inside SC were predictive for IOP reduction (p< 0.03 to < 0.001), but not for final IOP (p= 0.64 to 0.96).Conclusion. The angles of the inner wall of Schlemm’s canal generated by the suture stent were comparable between OCT and UBM and did not change significantly over time. There was a tendency towards a greater distension of Schlemm’s canal, when the difference was larger between pre- and postoperative IOP, suggesting the tensioning suture may contribute to IOP reduction.

The role of EP2 receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1

2020 ◽  
pp. bjophthalmol-2020-317762
Author(s):  
Jacques A Bertrand ◽  
David F Woodward ◽  
Joseph M Sherwood ◽  
Jenny W Wang ◽  
Darryl R Overby
Keyword(s):  
Intraocular Pressure ◽  
Ex Vivo ◽  
Hypotensive Activity ◽  
Long Term Effects ◽  
Gene Encoding ◽  
Knock Out ◽  
Pharmacological Mechanism ◽  
Knock Out Mice

BackgroundA single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular biodisposition or correlate with the once-daily dosing regimen for other prostanoid EP2 receptor agonists such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multiday extended activity of JV-GL1 is highly intriguing. The present studies were intended to determine EP2 receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP2 receptors.MethodsThe protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP2 receptor knock-out mice (B6.129-Ptger2tm1Brey/J; EP2KO). Both ocular normotensive and steroid-induced ocular hypertensive (SI-OHT) mice were studied. IOP was measured tonometrically under general anaesthesia. Aqueous humour outflow facility was measured ex vivo using iPerfusion in normotensive C57BL/6J mouse eyes perfused with 100 nM de-esterified JV-GL1 and in SI-OHT C57BL/6J mouse eyes that had received topical JV-GL1 (0.01%) 3 days prior.ResultsBoth the initial 1-day and the protracted multiday effects of JV-GL1 in the SI-OHT model for glaucoma were abolished by deletion of the gene encoding the EP2 receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP2KO mice, but in littermate SI-OHT EP2WT control mice, JV-GL1 statistically significantly lowered IOP for 4–6 days.ConclusionsBoth the 1-day and the long-term effects of JV-GL1 on IOP are entirely EP2 receptor dependent.

scholarly journals Androgen Receptor Expression in the Caput Epididymal Epithelium Is Essential for Development of the Initial Segment and Epididymal Spermatozoa Transit

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 718-729 ◽  
Author(s):  
Laura O'Hara ◽  
Michelle Welsh ◽  
Philippa T.K. Saunders ◽  
Lee B. Smith
Keyword(s):  
Androgen Receptor ◽  
Initial Segment ◽  
Serum Testosterone ◽  
Normal Serum ◽  
Receptor Expression ◽  
Obstructive Azoospermia ◽  
Knock Out ◽  
Knock Out Mice ◽  
And Function ◽  
The Impact

Abstract The epididymis plays an essential role in male fertility, and disruption of epididymal function can lead to obstructive azoospermia. Formation and function of the epididymis is androgen-dependent. The androgen receptor (AR) is expressed in both the stromal and epithelial compartments of the epididymis, and androgen action mediated via stromal cells is vital for its normal development and function. However the impact of epithelial specific AR-dependent signaling in the epididymis remains underexplored. To address this, we used conditional gene-targeting in mice to selectively ablate AR from the caput epididymal epithelium, and characterized the resulting phenotype at multiple postnatal ages. Caput epithelium androgen receptor knock-out mice have normal serum testosterone concentrations at day (d) 21 and d100, but do not develop an epididymal initial segment. The remaining caput epithelium displays a significant decrease in epithelial cell height from d11 and lumen diameter from d21 and disruption of the smooth muscle layer of the caput epididymis at d100. From d21, caput epithelium androgen receptor knock-out mice accumulate cell debris, proteinaceous material, and, at later ages, spermatozoa in their efferent ducts, which prevents normal passage of spermatozoa from the testis into the cauda epididymis resulting in infertility when tested at d100. This efferent duct obstruction leads to fluid back-pressure and disruption of the seminiferous epithelium of the adult testis. We conclude that epithelial AR signaling is essential for postnatal development and function of the epididymal epithelium and that disruption of this signaling can contribute to obstructive azoospermia.

Caveolins, caveolae, and lipid rafts in cellular transport, signaling, and disease

2004 ◽  
Vol 82 (1) ◽  
pp. 129-144 ◽  
Author(s):  
Andrew F.G Quest ◽  
Lisette Leyton ◽  
Mario Párraga
Keyword(s):  
Lipid Rafts ◽  
Structural Integrity ◽  
Membrane Microdomains ◽  
Cellular Transport ◽  
Knock Out ◽  
Caveolin 1 ◽  
Membrane Compartments ◽  
Knock Out Mice ◽  
And Function

Caveolae were initially described some 50 years ago. For many decades, they remained predominantly of interest to structural biologists. The identification of a molecular marker for these domains, caveolin, combined with the possibility to isolate such cholesterol- and sphingolipid-rich regions as detergent-insoluble membrane complexes paved the way to more rigorous characterization of composition, regulation, and function. Experiments with knock-out mice for the caveolin genes clearly demonstrate the importance of caveolin-1 and -3 in formation of caveolae. Nonetheless, detergent-insoluble domains are also found in cells lacking caveolin expression and are referred to here as lipid rafts. Caveolae and lipid rafts were shown to represent membrane compartments enriched in a large number of signaling molecules whose structural integrity is essential for many signaling processes. Caveolin-1 is an essential structural component of cell surface caveolae, important for regulating trafficking and mobility of these vesicles. In addition, caveolin-1 is found at many other intracellular locations. Variations in subcellular localization are paralleled by a plethora of ascribed functions for this protein. Here, more recent data addressing the role of caveolin-1 in cellular signaling and the development of diseases like cancer will be preferentially discussed.Key words: caveolae, rafts, membrane microdomains, caveolins, signal transduction, disease, cancer.

Carboxypeptidase U (TAFIa): a metallocarboxypeptidase with a distinct role in haemostasis and a possible risk factor for thrombotic disease

2005 ◽  
Vol 94 (09) ◽  
pp. 471-487 ◽  
Author(s):  
Judith Leurs ◽  
Dirk Hendriks
Keyword(s):  
Bleeding Tendency ◽  
Knock Out ◽  
Lysine Residues ◽  
Knock Out Mice ◽  
The Moment ◽  
And Function ◽  
Coagulation And Fibrinolysis

SummarySince the discovery of Carboxypeptidase U (CPU) in 1988, considerable information has been gathered about its biochemistry and function in physiological and pathophysiological circumstances. A variety of tools such as assays to measure proCPU and CPU, antibodies raised against (pro)CPU, selective CPU inhibitors and knock-out mice have been developed and are currently being used to explore the role of this metallocarboxypeptidase in different in vivo and in vitro settings. The knowledge that proCPU can be activated by thrombin and plasmin, enzymes with a key function in coagulation and fibrinolysis, and the ability of CPU to remove C-terminal lysine residues has led to the hypothesis that the proCPU/CPU pathway plays a role in the balance between coagulation and fibrinolysis. The maintenance of the equilibrium between coagulation and fibrinolysis is crucial for normal haemostasis and disturbance of this delicate balance can lead either to bleeding tendency or thrombosis. This review provides an update on several aspects of CPU known at the moment, including an extensive overview on the clinical studies performed up till now.J. Leurs is a research assistant of the Fund for Scientific Research Flanders (FWO-Vlaanderen).

scholarly journals Glycosylation Is Dispensable for Sorting of Synaptotagmin 1 but Is Critical for Targeting of SV2 and Synaptophysin to Recycling Synaptic Vesicles

2012 ◽  
Vol 287 (42) ◽  
pp. 35658-35668 ◽  
Author(s):  
Sung E. Kwon ◽  
Edwin R. Chapman
Keyword(s):  
Synaptic Vesicle ◽  
Post Translational Modification ◽  
Vesicle Membrane ◽  
Knock Out ◽  
Synaptic Localization ◽  
Glycosylation Sites ◽  
Synaptotagmin 1 ◽  
Knock Out Mice ◽  
And Function

Glycosylation is a major form of post-translational modification of synaptic vesicle membrane proteins. For example, the three major synaptic vesicle glycoproteins, synaptotagmin 1, synaptophysin, and SV2, represent ∼30% of the total copy number of vesicle proteins. Previous studies suggested that glycosylation is required for the vesicular targeting of synaptotagmin 1, but the role of glycosylation of synaptophysin and SV2 has not been explored in detail. In this study, we analyzed all glycosylation sites on synaptotagmin 1, synaptophysin, and SV2A via mutagenesis and optical imaging of pHluorin-tagged proteins in cultured neurons from knock-out mice lacking each protein. Surprisingly, these experiments revealed that glycosylation is completely dispensable for the sorting of synaptotagmin 1 to SVs whereas the N-glycans on SV2A are only partially dispensable. In contrast, N-glycan addition is essential for the synaptic localization and function of synaptophysin. Thus, glycosylation plays distinct roles in the trafficking of each of the three major synaptic vesicle glycoproteins.

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

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