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Multi-organ protection from hyperoxia of the severely premature infant

Award Number: R01EY024972
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Multi-organ protection from hyperoxia of the severely premature infant - Abstract The broad, long-term objective of this proposal is to develop a safe method of protecting retinal blood vessels from oxygen induced toxicity that accompanies premature birth. Oxygen therapy is necessary to prevent mortality in these infants but is harmful to premature retinal tissue. Oxygen toxicity to the premature retina, known as retinopathy of prematurity (ROP), blinds 150,000- 200,000 children worldwide annually. Quantitative analysis of retinal and lung vasculature in mouse and rat models of human ROP demonstrate that preservation of hypoxia inducible factor (HIF) activity through HIF prolyl hydroxylase domain protein (PHD) inhibition (HIF PHi) safely prevents oxygen-induced lung disease, hypomyelination of the central nervous system, and retinopathy (OIR). We have definitively demonstrated that our systemic strategy of PHD inhibition requires liver specific HIF-1α activation. Our studies have demonstrated that the fetal liver uses HIF induced 1C metabolism (1CM) to protect distal capillary beds from oxygen induced growth suppression. These findings make liver specific HIF PHi a unified approach to preventing ROP by biochemically addressing both hyperoxia of prematurity (by stabilizing HIF in hyperoxia) and separation from the maternal circulation (by stimulating the liver to upregulate protective metabolic pathways). The specific goal of this application is to enable the premature infant to benefit from oxygen supplementation (reducing mortality) by creating a liver specific small molecule to stimulate the oxygen sensor in the severely premature infant to protect it from excess oxygen. Results from these studies will create a therapy to protect severely premature infants and eradicate retinopathy of prematurity while developing a strategy that might revascularize ischemic tissues.


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: 2025 ( Subtotal = $402,500 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	001	9	5/30/2025	COMPETING CONTINUATION	$402,500
2025	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	8	3/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,500

Issue Date FY: 2023 ( Subtotal = $402,500 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	8	7/13/2023	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2022 ( Subtotal = $390,425 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	001	7	7/28/2022	NON-COMPETING CONTINUATION	$390,425
2022	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	6	10/15/2021	COMPETING CONTINUATION	$0
														Subtotal = $390,425

Issue Date FY: 2021 ( Subtotal = $402,496 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	001	6	9/21/2021	COMPETING CONTINUATION	$402,500
2021	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	5	2/13/2021	NON-COMPETING CONTINUATION	-$4
														Subtotal = $402,496

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	5	7/24/2019	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2018 ( Subtotal = $396,250 )
2018	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	4	7/13/2018	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2017 ( Subtotal = $396,250 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	3	7/24/2017	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2016 ( Subtotal = $396,250 )
2016	2016	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	2	8/18/2016	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2015 ( Subtotal = $396,250 )
2015	2015	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Vision Research	000	1	7/17/2015	NEW	$396,250
														Subtotal = $396,250

Grand Total All Awards = $3,579,171

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Multi-organ protection from hyperoxia of the severely premature infant

Award Number: R01EY024972

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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