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The Role of Ezrin in Schlemm’s Canal Cell Mechanobiology in Glaucoma

Award Number: K99EY038905
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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The Role of Ezrin in Schlemm’s Canal Cell Mechanobiology in Glaucoma - Primary open-angle glaucoma is a leading cause of irreversible blindness, and ocular hypertension (OHT) is the only modifiable risk factor for glaucoma. Outflow resistance and intraocular pressure (IOP) are largely modulated by pores in the Schlemm’s canal (SC) inner wall and by the underlying trabecular meshwork (TM). SC pores include paracellular and transcellular types; this study focuses on transcellular pores (I-pores), which require dynamic plasma membrane (PM) remodeling. I-pore formation is mechanosensitive, promoted by mechanical stretch and perfusion, and closely tied to cell stiffness. In glaucoma, reduced I-pore density and changes in SC cell mechanobiology suggest that impaired SC cell mechanosensing contributes to OHT in glaucoma. Ezrin is a mechano-responsive protein that links PMs to the actin cytoskeleton and modulates actomyosin contractility and cell stiffness, processes closely associated with I-pore formation and outflow resistance. Additionally, ezrin has been shown to influence PM tension and intracellular Ca2+ levels, key modulators of membrane fusion events that are essential for I-pore formation in SC cells. Despite these connections, the specific role of ezrin in modulating aqueous humor outflow remains relatively unexplored. Preliminary data show that ezrin activity modulates SC cell stiffness and I-pore formation and alters SC responses to substrate stiffening, as occurs in glaucoma. The central hypothesis is that ezrin modulates SC cell responses to mechanical stimuli, including localized mechanical stretch and substrate stiffening, thereby affecting I-pore formation and outflow resistance. This hypothesis will be tested through three specific aims. Aim 1 will determine the role of ezrin in I-pore formation (using an established in vitro platform), IOP (in normotensive and OHT mouse models), and outflow facility (in cannulated mouse eyes using the iPerfusion system) during the K99 phase. Aim 2 will investigate how ezrin modulates SC cell responses to localized mechanical stretch, focusing on outcome measures closely related to membrane fusion and I-pore formation: PM tension and intracellular Ca2+ levels. Additionally, proximity labeling combined with mass spectrometry will be used to define the active ezrin interactome, further elucidating the molecular mechanisms by which ezrin modulates I-pore formation (R00 phase). Aim 3 will define how ezrin modulates SC cell responses to glaucomatous substrate stiffening. SC cells will be cultured on hydrogel substrates with varying tissue-level stiffnesses to assess how substrate stiffness influences ezrin activity and how ezrin, in turn, modulates stiffness-dependent mechanotransduction (R00 phase). During the mentored phase, the applicant will receive training in live animal models, SC-targeted drug delivery, ex vivo outflow facility measurement, viral-mediated gene delivery, and membrane tension analysis. This training will complement her strong foundation in glaucoma research and cell mechanobiology and support her transition to an independent academic career focused on SC cell mechanobiology and outflow modulation in glaucoma.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $126,530 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Vision Research	000	1	8/3/2026	NEW	$126,530
														Subtotal = $126,530

Grand Total All Awards = $126,530

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The Role of Ezrin in Schlemm’s Canal Cell Mechanobiology in Glaucoma

Award Number: K99EY038905

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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