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Fetal glucagon links fetal metabolism with uterine blood flow and placental nutrient transfer by inhibiting placental lactogen secretion

Award Number: R01HD111557
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/13/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Fetal glucagon links fetal metabolism with uterine blood flow and placental nutrient transfer by inhibiting placental lactogen secretion - PROJECT ABSTRACT Our goal is to establish a new framework for understanding the regulation of fetal growth. To do so, we will demonstrate novel roles for fetal glucagon and maternal placental lactogen. Current dogma holds that the mother's nutritional and hormonal status, uterine blood flow, and early events in placental development regulate placental nutrient delivery and fetal growth. However, knowledge gaps in this understanding have prevented progress towards successful treatment of disordered fetal growth during complications of pregnancy. This proposal will show how fetal glucagon inhibits uterine blood flow and placental nutrient delivery by inhibiting secretion of placental lactogen into the maternal circulation. We have recently demonstrated that experimentally increasing fetal glucagon concentrations with direct fetal glucagon infusions into late gestation fetal sheep lowers uterine blood, placental uptake of nutrients and oxygen from the maternal circulation, placental delivery of amino acids to the fetus, fetal plasma concentrations of amino acids, fetal plasma concentrations of the anabolic growth factors insulin and IGF-1, and fetal protein accretion. These were associated with a 13% reduction in fetal weight after just a nine-day infusion. Additionally, we have demonstrated that experimentally lowering placental lactogen in pregnant sheep results in lower uterine blood flow and placental nutrient delivery independent of its classically described role in regulating maternal nutrient metabolism. We have repeatedly shown that increasing fetal amino acids raises fetal glucagon concentrations. Taken together, these data support our overarching hypothesis: fetal glucagon matches placental nutrient delivery to fetal metabolic demand by inhibiting PL secretion. This hypothesis will be tested in pregnant sheep, isolated human primary trophoblasts, and uterine and myometrial arteries isolated from pregnant sheep and humans, respectively. In Aim #1 we will show that the mechanism by which fetal glucagon inhibits fetal growth is by lowering placental amino acid delivery and fetal amino acid concentrations. In Aim #2 we will demonstrate that the mechanism by which fetal glucagon inhibits uterine blood flow and placental nutrient delivery is by lowering placental lactogen secretion. In Aim #3 we will establish the mechanism by which glucagon inhibits placental lactogen secretion. This proposal will be the first mechanistic physiological investigation into fetal glucagon as an inhibitor of uterine blood flow, placental nutrient delivery, and fetal growth and placental lactogen as a vasodilator in the uterine circulation. The impact will be to shift the paradigm for our understanding of the regulation of fetal growth. This is required if we are to make new advances into the management of disordered fetal growth in pregnancies complicated by placental insufficiency, preeclampsia, diabetes, maternal obesity and other conditions.


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: 2026 ( Subtotal = $553,960 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Child Health and Human Development Extramural Research	000	4	1/7/2026	NON-COMPETING CONTINUATION	$553,960
														Subtotal = $553,960

Issue Date FY: 2025 ( Subtotal = $625,508 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Child Health and Human Development Extramural Research	000	3	1/16/2025	NON-COMPETING CONTINUATION	$562,958
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Child Health and Human Development Extramural Research	001	3	4/16/2025	NON-COMPETING CONTINUATION	$62,550
														Subtotal = $625,508

Issue Date FY: 2024 ( Subtotal = $643,595 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Child Health and Human Development Extramural Research	000	2	1/15/2024	NON-COMPETING CONTINUATION	$585,087
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Child Health and Human Development Extramural Research	001	2	6/17/2024	NON-COMPETING CONTINUATION	$58,508
														Subtotal = $643,595

Issue Date FY: 2023 ( Subtotal = $661,228 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Child Health and Human Development Extramural Research	000	1	4/13/2023	NEW	$661,228
														Subtotal = $661,228

Grand Total All Awards = $2,484,291

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Fetal glucagon links fetal metabolism with uterine blood flow and placental nutrient transfer by inhibiting placental lactogen secretion

Award Number: R01HD111557

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/13/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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