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Mechanisms of lens epithelium fibrosis and its relevance to posterior capsule opacification

Award Number: R01EY032488
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Mechanisms of lens epithelium fibrosis and its relevance to posterior capsule opacification - Abstract Cataract surgery is associated with a high risk of posterior capsule opacification (PCO), a form of secondary cataract, the formation of which is still poorly understood. However, PCO is generally considered a chronic disease and a consequence of the LEC fibrotic process, attributed in part to the epithelial-mesenchymal transition (EMT) in which TGFβ mediated signaling is one of the key players. Recently, we and others have suggested that canonical Wnt/β-catenin signaling is also a pivotal player in LEC fibrosis and the pathogenesis of PCO. To test the Wnt signaling in chronic conditions, we conducted a 6-month-kinetic rabbit cataract surgery study and found a profound activation of the canonical Wnt signaling during the course of PCO formation, associated with elevated oxidation and chronic inflammation. We postulate that lens epithelial cells (LECs) undergo self- regulatory signaling transduction to adapt to the new microenvironment after cataract surgery, and the canonical Wnt/β-catenin plays a pivotal role in this process. Our initial study identifies Wnt3 as a highly expressed and upregulated Wnt-family gene in human and mouse LECs after cataract surgery. However, the role of Wnt3 signaling mediated LEC fibrosis and PCO formation is still unclear; the underlying mechanisms of how lens epithelial cells regulate the Wnt signaling remain to be addressed. We plan to unravel these puzzles with a basis of support from several key findings of our pilot studies, e.g., our discovery that LECs package Wnt3 into exosomes, a type of extracellular vesicle (EVs), and conduct signaling transduction in an endocrine fashion. Importantly, inflammatory cytokines, such as TNFα, can drastically promote exosome biogenesis and Wnt3 secretion. Aim 1 will test how lens epithelial cells regulate Wnt3 packaging and exosome biogenesis. We need to understand how LECs manage to promote exosome biogenesis and Wnt3 secretion under the certain stimuli, e.g., inflammatory cytokines and oxidative stress. Aim 2 will delineate the role of Wnt3 in LEC proliferation, migration, and differentiation using in vitro cell culture, primary cell culture, ex vivo explant culture, and in vivo mouse models. Aim3 studies the LECs’ growth microenvironment and the Wnt3 mediated autocrine signaling by using human tissue with and without a history of cataract surgery. Human tissue studies will offer a final checkpoint of research after studies from cell culture and animal models. In summary, substantial pilot data form the basis of our proposal, one which will unravel a novel LECs self-regulatory pathway that is closely reminiscent of the pathological and physiological conditions of cataract surgery.


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 = $385,000 )
2026	2026	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	5	6/9/2026	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2025 ( Subtotal = $385,000 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	4	6/27/2025	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2024 ( Subtotal = $385,000 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	3	5/20/2024	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2023 ( Subtotal = $385,000 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	2	5/30/2023	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2022 ( Subtotal = $385,000 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	1	8/17/2022	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $1,925,000

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Mechanisms of lens epithelium fibrosis and its relevance to posterior capsule opacification

Award Number: R01EY032488

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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