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Perinatal NO signaling in congenital heart disease

Award Number: R01HL137282
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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Perinatal NO signaling in congenital heart disease - Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Children born with congenital heart defects that result in increased PBF develop abnormal pulmonary vascular reactivity. Although survival for these children has improved they continue to suffer morbidity and late mortality. This is due to the fact that they are at great risk for developing pulmonary vascular disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular reactivity, causes significant morbidity and mortality. Using an experimental lamb model of CHD with increased PBF (Shunt) we were the first to identify that decreased interactions between heat shock protein 90 (hsp90) and endothelial NO synthase (eNOS) plays a major role in the reduced nitric oxide (NO) signaling associated with this disease. Our data implicate decreases in hsp90 activity as well as an increase in eNOS nitration in this process. In addition, our published data indicate that the loss of hsp90 activity correlates with the disruption of the eNOS dimeric structure. Based on these data, the overall hypothesis we will test is that eNOS nitration disrupts its interaction with hsp90 leading to dimer disruption and decreased NO generation. Further, we will investigate if stimulating hsp90 activity will restore NO signaling and endothelial function. Our investigations will be carried out in three interrelated, but independent, Aims. We will utilize a translational approach that will integrate biophysical, cellular and whole animal studies. The successful completion of our studies should yield new mechanistic insights and will identify new targets that are amenable to therapeutic intervention.


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: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	4	7/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	4	6/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $682,425 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	4	3/6/2020	NON-COMPETING CONTINUATION	$682,425
														Subtotal = $682,425

Issue Date FY: 2019 ( Subtotal = $682,425 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	3	4/5/2019	NON-COMPETING CONTINUATION	$682,425
														Subtotal = $682,425

Issue Date FY: 2018 ( Subtotal = $682,425 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	2	2/21/2018	NON-COMPETING CONTINUATION	$668,777
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	2	6/23/2018	NON-COMPETING CONTINUATION	$13,648
														Subtotal = $682,425

Issue Date FY: 2017 ( Subtotal = $689,715 )
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	1	3/6/2017	NEW	$689,715
														Subtotal = $689,715

Grand Total All Awards = $2,736,990

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Perinatal NO signaling in congenital heart disease

Award Number: R01HL137282

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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