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Mechanisms of newborn pulmonary hypertension caused by chronic intrauterine hypoxia

Award Number: R01HL155295
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Mechanisms of newborn pulmonary hypertension caused by chronic intrauterine hypoxia - PROJECT SUMMARY Chronic intrauterine hypoxia is common amongst not only the 140 million people in the world living at high altitudes but also in many complications of pregnancy such as preeclampsia, cigarette smoking, and placental insufficiency. Adaptation of the fetus to chronic hypoxia results in many adverse developmental outcomes, including pulmonary hypertension of the newborn. The BKCa channel is critical to the relaxation of the pulmonary vasculature of the newborn at birth. Recent results from our well-established fetal lamb model of chronic hypoxia during pregnancy points to BKCa channel dysfunction as a causal factor in pulmonary hypertension. The work in this proposal will investigate the mechanistic link between cellular hypoxia and BKCa channel dysfunction. Recent work by others indicates that the ‘master hypoxamir’ miR210, a micro-RNA that is upregulated by HIF-1?, orchestrates pulmonary hypertension by suppressing translation of the iron-sulfur cluster assembly protein ISCU. The resulting lack of iron-sulfur clusters results in mitochondrial dysfunction. We hypothesize that chronic intrauterine hypoxia leads to pulmonary hypertension by activation of the HIF-1? → miR210 → ISCU axis, resulting in increased mitochondrial-derived reactive oxygen species that lead to BKCa channel dysfunction. We propose three specific aims. Each specific aim is designed to integrate in vitro and in vivo approaches in order to better ascertain the relevance of the in vitro results to pulmonary function of the intact animal. Aim 1 will focus on determining the mechanism underlying BKCa channel dysfunction, and on establishing whether loss of BKCa channel function alone is adequate to result in pulmonary hypertension in intact lambs. Aim 2 will focus on the effects of hypoxia-induced increases in miR210 on ISCU activity, iron-sulfur cluster levels, and mitochondrial function and reactive oxygen species production. In intact lambs, we will establish whether activation of this pathway in the absence of hypoxia results in pulmonary hypertension, and whether suppression of this pathway in the presence of hypoxia prevents BKCa channel function and pulmonary hypertension. Aim 3 will investigate whether the increased reactive oxygen species levels in response to chronic hypoxia play a causative role in BKCa channel function and pulmonary hypertension. Using both in vitro and in vivo methods, we will determine whether the global antioxidant Vitamin C or mitochondria-specific antioxidant MitoQ will prevent pulmonary hypertension caused by chronic intrauterine hypoxia.


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 = $686,870 )
2025	2025	LOMA LINDA UNIVERSITY	11145 ANDERSON ST STE 203	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Lung Diseases Research	000	4	11/21/2024	NON-COMPETING CONTINUATION	$686,870
														Subtotal = $686,870

Issue Date FY: 2024 ( Subtotal = $755,914 )
2024	2024	LOMA LINDA UNIVERSITY	11145 ANDERSON ST	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Lung Diseases Research	001	3	7/11/2024	NON-COMPETING CONTINUATION	$61,708
2024	2024	LOMA LINDA UNIVERSITY	11145 ANDERSON ST	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Lung Diseases Research	000	3	12/1/2023	NON-COMPETING CONTINUATION	$694,206
														Subtotal = $755,914

Issue Date FY: 2023 ( Subtotal = $781,572 )
2023	2023	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Lung Diseases Research	001	2	3/10/2023	NON-COMPETING CONTINUATION	$78,157
2023	2023	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Lung Diseases Research	000	2	12/2/2022	NON-COMPETING CONTINUATION	$703,415
														Subtotal = $781,572

Issue Date FY: 2022 ( Subtotal = $797,486 )
2022	2022	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Lung Diseases Research	001	1	2/3/2022	NEW	$7,500
2022	2022	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Lung Diseases Research	000	1	12/22/2021	NEW	$789,986
														Subtotal = $797,486

Grand Total All Awards = $3,021,842

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Mechanisms of newborn pulmonary hypertension caused by chronic intrauterine hypoxia

Award Number: R01HL155295

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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