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FGF and hyaluronan-mediated alterations in epithelial-mesenchymal transition and metabolism of RPE cells in Sorsby Fundus Dystrophy.

Award Number: R01EY027083
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Sorsby fundus dystrophy (SFD) is a dominantly inherited, degenerative disease of the macula that is characterized by bilateral loss of central vision as a consequence of RPE dystrophy and choroidal neovascularization (CNV). Specific mutations in the TIMP-3 gene involving exon 5 or the intron4-exon5 boundary have been shown to be causative. The age-related macular degeneration (AMD) consortium has identified rare coding variants in the TIMP3 gene when analyzing 16,144 patients and 17,832 controls. The clinical and histopathological similarities between AMD and SFD and the identification of variants in the matrix metalloproteinase pathway in AMD suggest that similar downstream effectors might be in play in both conditions. A better understanding of the pathophysiological mechanisms contributing to the CNV in SFD will provide information that could be potentially useful in AMD. In comparative studies using TIMP-3 deficient mice, S179CTIMP-3 transgenic mice and in vitro culture experiments we have determined that RPE cells expressing mutant TIMP3 undergo epithelial-mesenchymal transformation (EMT) and have altered metabolism. These changes are correlated with increased bFGF and hyaluronan deposition. Based on these results, we hypothesize that under physiological conditions, TIMP3 is required to control and localize matrix degradation in the RPE/choroid which keeps the RPE in an epithelial state and allows for normal metabolic activity. Loss of TIMP3 function in this regard leads to EMT and altered metabolism which could have significant effects on RPE and retinal health.


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: 2024 ( Subtotal = $609,084 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	8	4/9/2024	NON-COMPETING CONTINUATION	$609,084
														Subtotal = $609,084

Issue Date FY: 2023 ( Subtotal = $610,140 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	001	7	3/27/2023	NON-COMPETING CONTINUATION	$610,140
2023	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	4	11/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $610,140

Issue Date FY: 2022 ( Subtotal = $621,747 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	002	6	6/6/2022	NON-COMPETING CONTINUATION	$621,747
2022	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	001	5	4/4/2022	COMPETING CONTINUATION	$22,384
2022	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	4	4/4/2022	NON-COMPETING CONTINUATION	-$22,384
														Subtotal = $621,747

Issue Date FY: 2021 ( Subtotal = $656,227 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	001	5	5/21/2021	COMPETING CONTINUATION	$656,227
2021	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	4	5/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $656,227

Issue Date FY: 2020 ( Subtotal = $396,250 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	4	3/19/2020	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2019 ( Subtotal = $396,250 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	3	3/25/2019	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2018 ( Subtotal = $356,625 )
2018	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	2	4/11/2018	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $356,625

Issue Date FY: 2017 ( Subtotal = $356,625 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	1	3/9/2017	NEW	$356,625
														Subtotal = $356,625

Grand Total All Awards = $4,002,948

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FGF and hyaluronan-mediated alterations in epithelial-mesenchymal transition and metabolism of RPE cells in Sorsby Fundus Dystrophy.

Award Number: R01EY027083

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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