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Regulation and role of leptin in preeclampsia

Award Number: R01HL169576
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Regulation and role of leptin in preeclampsia - Preeclampsia (PE) is a hypertensive disease in pregnancy that is a leading cause of adverse maternal and fetal outcomes in the US. Decades of clinical studies demonstrate that levels of the adipokine leptin inappropriately increase, independent of body mass, in PE patients. However, whether leptin plays a role in the cardiovascular and fetal outcomes of PE is unknown. We recently established a mouse model of leptin-induced PE, in which exogenous leptin administration induces the clinical characteristics of PE in endothelial dysfunction, hypertension, placental mitochondrial dysfunction and fetal growth restriction when given in mid-late gestation pregnant mice. The goal of this proposal is to address a critical gap in knowledge regarding the stimuli upregulating leptin in PE and to investigate mechanisms via which leptin induces adverse maternal and fetal adaptations. Our central hypothesis is that sFlt-1 induces hyperleptinemia in PE, which promotes hypertension and fetal growth restriction via endothelial dysfunction. Placental ischemia is a key initiating event in PE and induces an anti-angiogenic milieu, most notably increasing soluble FMS like tyrosine kinase-1 (sFlt-1), the soluble form of vascular endothelial growth factor receptor 1 (VEGFR1). We show novel preliminary data that sFlt-1 increases leptin production in both humans and mice. We also demonstrate that placental ischemia, induced in the Reduced Uterine Perfusion Pressure (RUPP) mouse model of PE, increases circulating leptin as well as sFlt-1. We will test in Aim 1 whether placental ischemia increases leptin levels via sFlt-1, which mediates placental ischemia-induced endothelial and placental dysfunction. In this Aim, we propose that the RUPP mouse develops endothelial dysfunction, hypertension, placental mitochondrial dysfunction and fetal growth restriction, characteristics of PE, via leptin-mediated mechanisms. We will additionally investigate whether sFlt-1 sequestration of VEGF reduces VEGF receptor signaling and promotes leptin production in PE. Additional innovative preliminary data shows that endothelial leptin receptor activation increases the production of endothelin converting enzyme-1 (ECE-1) and endothelin-1 (ET-1) in pregnant mice. We further demonstrate that leptin upregulates endothelial mineralocorticoid receptor expression, which we have published decreases ECE-1 expression. Therefore, in Aim 2 we will test whether leptin induces PE characteristics via endothelial ET-1-mediated endothelial dysfunction. We will utilize mice with endothelial mineralocorticoid receptor deletion as well as endothelial leptin receptor knockout mice to determine whether leptin-induced ET-1 expression by these endothelial pathways leads to PE characteristics in pregnant mice. We will further determine whether ECE-1 induces vascular endothelial dysfunction and whether ECE-1 or ET-1 receptor antagonism ablates leptin-induced PE. Collectively, the results of Aim 1 and 2 will significantly move forward the field of leptin in PE and will give preclinical evidence if regulatory or downstream mechanisms of leptin in PE are potential therapeutics to improve clinical care of PE patients.


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 = $530,727 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	3	6/26/2025	NON-COMPETING CONTINUATION	$53,073
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	4/21/2025	NON-COMPETING CONTINUATION	$477,654
														Subtotal = $530,727

Issue Date FY: 2024 ( Subtotal = $520,113 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	4/15/2024	NON-COMPETING CONTINUATION	$477,654
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	2	6/20/2024	NON-COMPETING CONTINUATION	$42,459
														Subtotal = $520,113

Issue Date FY: 2023 ( Subtotal = $530,727 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	5/31/2023	NEW	$530,727
														Subtotal = $530,727

Grand Total All Awards = $1,581,567

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Regulation and role of leptin in preeclampsia

Award Number: R01HL169576

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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