Assessment of Aqueous Humor Dynamics in the Mouse by a Novel Method of Constant-Flow Infusion

Millar, J. A.; Clark, Abbot F.; Pang, Iok‐Hou

doi:10.1167/iovs.10-6069

Cited by 95 publications

(134 citation statements)

References 55 publications

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“…Our findings that hemizygosity for Tek is sufficient to cause disease in mice and that heterozygosity for LoF mutations is associated with PCG of varying severity in patients suggest, for the first time to our knowledge, that there exists a dosage sensitivity for reduced activity of the receptor. It is reported that the conventional outflow path for AH drainage (i.e., SC) plays a less important role in mice than in humans, underscoring the significance of finding elevated IOP in the hemizygous mouse model and suggesting similar structural defects in SC would cause more severe disease in patients (57)(58)(59). Finally, our data indicate that TEK "dose" might be particularly important for proper development of the vasculature of the anterior chamber of the eye, suggesting that regulation of TEK signal strength may be a therapeutic option.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

Souma¹,

Tompson²,

Thomson³

et al. 2016

Journal of Clinical Investigation

175

191

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Section: Discussionmentioning

confidence: 99%

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

Souma¹,

Tompson²,

Thomson³

et al. 2016

Journal of Clinical Investigation

175

191

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“…Aqueous humor outflow facility was measured after 1 mo of intravitreal virus injections in both eyes of each animal (age 4-5 mo) by constant flow infusion as described previously (46). In brief, anesthetized eyes were infused at a flow rate of 0.1 μL/min.…”

Section: Methodsmentioning

confidence: 99%

CRISPR-Cas9–based treatment of myocilin-associated glaucoma

Jain

Zode

Kasetti

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

135

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Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss worldwide, with elevated intraocular pressure (IOP) a major risk factor. Myocilin (MYOC) dominant gain-offunction mutations have been reported in ∼4% of POAG cases. MYOC mutations result in protein misfolding, leading to endoplasmic reticulum (ER) stress in the trabecular meshwork (TM), the tissue that regulates IOP. We use CRISPR-Cas9-mediated genome editing in cultured human TM cells and in a MYOC mouse model of POAG to knock down expression of mutant MYOC, resulting in relief of ER stress. In vivo genome editing results in lower IOP and prevents further glaucomatous damage. Importantly, using an ex vivo human organ culture system, we demonstrate the feasibility of human genome editing in the eye for this important disease.myocilin | CRISPR | glaucoma | trabecular meshwork | genome editing

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“…22 In these relatively short-term studies (20-min perfusions at each pressure level with a total study of only a few hours), no IOP homeostatic changes were observed and the return to low (15 mm Hg) pressure value was approximately the same as the initial value at that pressure. [22][23][24] In one study, similar facilities were obtained in the same mouse when anesthetized compared with when euthanatized. 24 In addition, short-term mechanical stretching lasting less than 6 h does not trigger any homeostatic response, as judged by biochemical readouts.…”

Section: Short-term Moderate Pressure Responsesmentioning

confidence: 99%

“…[22][23][24] In one study, similar facilities were obtained in the same mouse when anesthetized compared with when euthanatized. 24 In addition, short-term mechanical stretching lasting less than 6 h does not trigger any homeostatic response, as judged by biochemical readouts. 18 …”

Section: Short-term Moderate Pressure Responsesmentioning

confidence: 99%

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

Acott

Kelley

Keller

et al. 2014

Journal of Ocular Pharmacology and Therapeutics

140

146

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Although glaucoma is a relatively common blinding disease, most people do not develop glaucoma. A robust intraocular pressure (IOP) homeostatic mechanism keeps ocular pressures within relatively narrow acceptable bounds throughout most peoples' lives. The trabecular meshwork and/or Schlemm's canal inner wall cells respond to sustained IOP elevation and adjust the aqueous humor outflow resistance to restore IOP to acceptable levels. It appears that the cells sense IOP elevations as mechanical stretch or distortion of the actual outflow resistance and respond by initiating a complex extracellular matrix (ECM) turnover process that takes several days to complete. Although considerable information pertinent to this process is available, many aspects of the IOP homeostatic process remain to be elucidated. Components and mechanisms beyond ECM turnover could also be relevant to IOP homeostasis, but will not be addressed in detail here. Known aspects of the IOP homeostasis process as well as possible ways that it might function and impact glaucoma are discussed. Glaucoma Glaucoma is an optic neuropathy characterized by a distinctive pattern of permanent visual field loss. 1,2Optic disk cupping is also a diagnostic parameter. Elevated intraocular pressure (IOP) is the primary risk factor for glaucomatous optic nerve damage and reducing pressure remains the only treatable component of disease progression.2,3 Although glaucoma is a relatively common blinding disease affecting over 67 million persons worldwide, [3][4][5] it is noteworthy that only 2%-8% of people actually develop this disease within their lifetime and most only at advanced ages. The implication of this observation is that some very efficacious mechanism exists to maintain IOP within acceptable ranges throughout the life of most people. 6Intraocular Pressure IOP is maintained primarily by changes in the aqueous humor outflow resistance, which is thought to reside predominantly within the cribriform or juxtacanalicular ( JCT) region of the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC).6-10 Aqueous humor inflow rates are relatively stable and are not pressure dependent, until very high pressures are achieved. 11,12 Although outflow through the alternative or uveoscleral pathway is clearly important, most of the outflow in humans is through the conventional TM/SC route. 2,7,8,12,13 IOP HomeostasisFor our purposes, in this study, we will define IOP homeostasis as corrective adjustments of the aqueous humor outflow resistance, which occur in direct response to sustained pressure changes and which maintain IOP within acceptable physiological ranges.We hypothesize that the flow resistance within the conventional outflow pathway is continually being adjusted with time frames measured in many hours and that sustained pressure changes serve as a guide for the direction and extent of homeostatic resistance modifications. Since the outflow resistance is thought to be comprised primarily of extracellular matrix (ECM) 6,7,9,10,14,15 and sinc...

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Assessment of Aqueous Humor Dynamics in the Mouse by a Novel Method of Constant-Flow Infusion

Abstract: In this study, a unique technique was developed to concurrently assess IOP, C, Pe, Fin, and Fu in the mouse eye. This experimental approach should be useful to evaluate effects of pharmacologic agents or genetic manipulations on aqueous humor dynamics in mice and other animal models.

Cited by 95 publications

References 55 publications

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

CRISPR-Cas9–based treatment of myocilin-associated glaucoma

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

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