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NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult

Award Number: R01HL151187
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult - PROJECT ABSTRACT Recent advances in neonatal medicine have increased the population of low birth weight (LBW) babies that are incredibly susceptible for development of hypertension, cardiovascular disease and chronic kidney disease for unknown reasons as they mature through adulthood. Using an undernourished pregnant mouse model to generate LBW offspring that develop pathologies similar to those in LBW humans, the proposed studies will investigate the association of vascular and kidney disease in the LBW adult with systems regulated by oxidative stress. The study will also examine new potential therapeutic strategies that target vascular oxidant- regulated mechanisms to treat hypertension and renal dysfunction. Our current studies have provided evidence for NADPH oxidase-4 (NOX4) driven increases in superoxide-mediated endothelial nitric oxide dysfunction, thiol oxidation-mediated release of HMGB1 (which potentially activates TLR4) and IL-1β promoted inflammation as potential driving factors in the disease progression that the LBW adult experiences. Studies in Aim 1 will examine the consequences of LBW in Nox4 deficient mice and in LBW mice treated with agents that inhibit NOX4, scavenge superoxide (including superoxide in the mitochondrial matrix), stabilize cytosolic NADPH redox, and promote heme biosynthesis to define their impact on vascular dysfunction, impairment of renal perfusion and hypertension development. Measurements of a) redox and metabolic indicators or signaling mechanisms related to these approaches, b) alterations in vascular function, and c) alterations in tissue mitochondrial respiration and function will be made to help define driving forces in the progression of vascular and renal dysfunction that is observed. Using mice deficient in TLR4, and animals treated with inhibitors of HMGB1 release, TLR4 and IL-1β, studies in Aim 2 will focus on defining the role that the redox sensor HMGB1 has in causing inflammation, vascular rarefaction, renal fibrosis and glomerular hypertrophy associated with hypertension and kidney disease. Supporting mechanisms for the HMGB1-TLR4 activation processes will be defined in cells cultured from control and LBW animals. Studies in this aim will examine the role of TLR4 in the actions of oxidized forms of HMGB1, and the impact of TLR4 activation on endothelial cell mitochondrial dysfunction and release of IL-1β. The approaches and measurements made in Aim 1 will also be used to document the impact of the interventions in Aim 2 on relationships between redox regulatory processes and aspects of disease progression. It is hypothesized that the redox changes in HMGB1 (identified by mass spectral analyses) can potentially be modulated by the therapies employed in ways that could help define the HMGB1 redox forms that are the most pathologically active. It is anticipated that the studies proposed will document and define the driving factors that promote the progression of hypertension, cardiovascular and chronic kidney disease in LBW adults, in addition to identifying novel therapeutic approaches that target the systems that drive such disease progression.


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 = $0 )
2025	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	4	11/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $410,000 )
2023	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	001	4	2/11/2023	NON-COMPETING CONTINUATION	$41,000
2023	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	4	11/18/2022	NON-COMPETING CONTINUATION	$369,000
														Subtotal = $410,000

Issue Date FY: 2022 ( Subtotal = $410,000 )
2022	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	3	11/19/2021	NON-COMPETING CONTINUATION	$369,000
2022	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	001	3	6/8/2022	NON-COMPETING CONTINUATION	$41,000
														Subtotal = $410,000

Issue Date FY: 2021 ( Subtotal = $410,000 )
2021	2021	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	001	2	5/24/2021	NON-COMPETING CONTINUATION	$41,000
2021	2021	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	2	12/21/2020	NON-COMPETING CONTINUATION	$369,000
														Subtotal = $410,000

Issue Date FY: 2020 ( Subtotal = $410,000 )
2020	2020	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	1	12/9/2019	NEW	$410,000
														Subtotal = $410,000

Grand Total All Awards = $1,640,000

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NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult

Award Number: R01HL151187

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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