siRNA targeting Schlemm's canal endothelial tight junctions enhances outflow facility and reduces IOP in a steroid-induced OHT rodent model.
siRNA targeting Schlemm's canal endothelial tight junctions enhances outflow facility and reduces IOP in a steroid-induced OHT rodent model.
复制标题
靶向Schlemm管内皮紧密连接的siRNA在类固醇诱导的OHT啮齿动物模型中增强流出功能并降低IOP
DOI：
10.1016/j.omtm.2020.10.022
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发表时间：
2021-03-12
期刊：
影响因子：
--
通讯作者：
O'Callaghan J
中科院分区：
文献类型：
--
作者：
Cassidy PS;Kelly RA;Reina-Torres E;Sherwood JM;Humphries MM;Kiang AS;Farrar GJ;O'Brien C;Campbell M;Stamer WD;Overby DR;Humphries P;O'Callaghan J
全身或局部应用糖皮质激素（GC）可导致医源性高眼压，这是继发性开角型青光眼和视力损害的主要原因。先前的工作已经表明，地塞米松增加小梁网（TM）细胞中的闭锁小带-1（ZO-1）蛋白表达，ZO-1的反义寡核苷酸抑制剂可以消除地塞米松诱导的培养的Schlemm管（SC）内皮细胞和TM细胞中跨内皮流动阻力的增加。我们以前已经表明，前房内接种小干扰RNA（siRNA）靶向SC内皮细胞紧密连接的组件，ZO-1和三纤维素，增加房水流出设施离体血压正常小鼠可逆地打开SC内皮细胞旁孔。在这项研究中，我们表明，这些SC内皮紧密连接的靶向siRNA下调降低眼内压（IOP）在体内，伴随着传统的外流设施增加，在一个良好的特征性慢性类固醇诱导的高眼压小鼠模型，因此代表了一个潜在的集中在视力威胁的情况下，这种疗法的临床应用。Cassidy及其同事表明，前房内接种靶向Schlemm管内皮细胞紧密连接蛋白ZO-1和三纤维素的siRNA，可以降低类固醇诱导的高眼压小鼠模型的眼内压并增加流出功能。
Systemic or localized application of glucocorticoids (GCs) can lead to iatrogenic ocular hypertension, which is a leading cause of secondary open-angle glaucoma and visual impairment. Previous work has shown that dexamethasone increases zonula occludens-1 (ZO-1) protein expression in trabecular meshwork (TM) cells, and that an antisense oligonucleotide inhibitor of ZO-1 can abolish the dexamethasone-induced increase in trans-endothelial flow resistance in cultured Schlemm’s canal (SC) endothelial and TM cells. We have previously shown that intracameral inoculation of small interfering RNA (siRNA) targeting SC endothelial cell tight junction components, ZO-1 and tricellulin, increases aqueous humor outflow facility ex vivo in normotensive mice by reversibly opening SC endothelial paracellular pores. In this study, we show that targeted siRNA downregulation of these SC endothelial tight junctions reduces intraocular pressure (IOP) in vivo, with a concomitant increase in conventional outflow facility in a well-characterized chronic steroid-induced mouse model of ocular hypertension, thus representing a potential focused clinical application for this therapy in a sight-threatening scenario. Cassidy and colleagues show that intracameral inoculation of siRNA targeting Schlemm’s canal endothelial cell tight junction proteins, ZO-1 and tricellulin, can reduce intraocular pressure and increase outflow facility in a murine model of steroid-induced ocular hypertension.
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影响因子：
4.4
作者：
Yuan, Yong;Call, Mindy K.;Kao, Winston W. -Y.
通讯作者：
Kao, Winston W. -Y.
影响因子：
3.4
作者：
Overby DR;Clark AF
通讯作者：
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流出阻力产生的不断变化的范式：朝向JCT和内壁内皮的协同模型。
影响因子：
3.4
作者：
Overby, Darryl R.;Stamer, W. Daniel;Johnson, Mark
通讯作者：
Johnson, Mark
DOI：
10.1073/pnas.1410602111
发表时间：
2014-09-23
影响因子：
11.1
作者：
Overby, Darryl R.;Zhou, Enhua H.;Johnson, Mark
通讯作者：
Johnson, Mark
类固醇引起的青光眼：可避免的不可逆转的失明。
影响因子：
--
作者：
Phulke S;Kaushik S;Kaur S;Pandav SS
通讯作者：
Pandav SS