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Investigation of regulatory cascades governing development of the outflow structures of the eye

Award Number: R01EY025789
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Investigation of regulatory cascades governing development of the outflow structures of the eye - Anterior segment dysgenesis (ASD) is a developmental anomaly of the eye that can involve multiple tissues including the cornea, iris, lens, ciliary body and ocular drainage structures including the trabecular meshwork (TM). As a result, ASD is associated with an increased risk of glaucoma and corneal opacities. In fact, glaucoma will arise in 50% of patients with ASD due to disruption in aqueous humour drainage, which leads to an elevation in intraocular pressure (IOP). Malformation of structures in the anterior segment of the eye is thought to occur due to a defect in the differentiation and migration of the periocular mesenchyme (POM), a derivative of neural crest. Although inappropriate patterning of the POM is strongly implicated in ASD, the mechanisms of POM function and/or disruption in ASD are unclear. Our laboratories have shown that activating transcription factor β (AP-2β) is highly expressed in the POM and POM-derived tissues of the post- natal mouse eye. During the previous funding period we created two mouse models in which Tfap2b (the gene encoding AP-2β) was conditionally deleted in the POM. These models both exhibit features reminiscent of human ASD and glaucoma. However, one model presents with complete iridocorneal adhesion, and the other with a partially closed angle phenotype, yet in both models the TM region is severely affected. We further utilized one of these models to identify important, candidate downstream genes of AP-2β that likely impact development of anterior eye structures. The current proposal aims to employ these novel models to further determine how loss of function of AP-2β results in developmental defects and alterations in downstream regulatory networks that control formation of the anterior angle structures of the eye, which are critical in managing aqueous outflow. Thus, our overarching hypothesis is that AP-2β-regulated genetic cascades in the POM are essential for governing development of the ocular structures in the anterior segment of the eye that maintain IOP homeostasis. In the current proposal we will continue to utilize conditional KO approaches in mice to identify the individual role(s) that the AP-2β gene plays in development of the anterior angle tissues including the TM. We will also use state-of-the-art “omics” level analyses to determine the patterns of normal gene expression in the anterior segment and how they are disrupted by loss of Tfap2b. Finally, we will further assess the glaucomatous changes observed in the mouse models generated to further understand the pathophysiology of closed angle glaucoma and optic neuropathy.


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: 2023 ( Subtotal = $364,057 )
2023	2023	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON			CAN	Vision Research	000	8	5/1/2023	NON-COMPETING CONTINUATION	$364,057
														Subtotal = $364,057

Issue Date FY: 2022 ( Subtotal = $368,218 )
2022	2022	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON			CAN	Vision Research	000	7	4/18/2022	NON-COMPETING CONTINUATION	$368,218
														Subtotal = $368,218

Issue Date FY: 2021 ( Subtotal = $364,447 )
2021	2021	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON			CAN	Vision Research	000	6	5/13/2021	NON-COMPETING CONTINUATION	$364,447
														Subtotal = $364,447

Issue Date FY: 2020 ( Subtotal = $373,399 )
2020	2020	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON	L8S 4L8		CAN	Vision Research	002	5	9/2/2020	COMPETING CONTINUATION	$62,893
2020	2020	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON	L8S 4L8		CAN	Vision Research	000	5	4/22/2020	COMPETING CONTINUATION	$310,506
2020	2018	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON	L8S 4L8		CAN	Vision Research	001	4	7/16/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $373,399

Issue Date FY: 2018 ( Subtotal = $367,445 )
2018	2018	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON	L8S 4L8		CAN	Vision Research	000	4	8/23/2018	NON-COMPETING CONTINUATION	$318,845
2018	2018	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON	L8S 4L8		CAN	Vision Research	001	4	9/24/2018	SUPPLEMENT FOR EXPANSION	$48,600
														Subtotal = $367,445

Issue Date FY: 2017 ( Subtotal = $318,845 )
2017	2017	MCMASTER UNIVERSITY	1280 MAIN ST W SUITE 20	HAMILTON	ON	L8S 4L8		CAN	Vision Research	000	3	8/24/2017	NON-COMPETING CONTINUATION	$318,845
														Subtotal = $318,845

Issue Date FY: 2016 ( Subtotal = $333,815 )
2016	2016	MCMASTER UNIVERSITY	1200 MAIN STREET WEST	HAMILTON				CAN	Vision Research	000	2	8/17/2016	NON-COMPETING CONTINUATION	$333,815
														Subtotal = $333,815

Issue Date FY: 2015 ( Subtotal = $333,815 )
2015	2015	MCMASTER UNIVERSITY	1200 MAIN STREET WEST	HAMILTON				CAN	Vision Research	000	1	9/7/2015	NEW	$333,815
														Subtotal = $333,815

Grand Total All Awards = $2,824,041

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Investigation of regulatory cascades governing development of the outflow structures of the eye

Award Number: R01EY025789

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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