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Liver Diseases and Pregnancy Complications

Award Number: R01DK139489
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Liver Diseases and Pregnancy Complications - As an organ responsible for nutritional and energy metabolism, liver plays important roles in maintaining normal pregnancy. Liver diseases during pregnancy is relatively poorly studied and represents one of the gaps for liver research. Approximately 3-5% of pregnant women are affected by liver diseases during pregnancy. When severe, those liver diseases are associated with significant morbidity and mortality for both mother and infant. Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease unique to pregnancy while non- alcoholic fatty liver disease (NAFLD) is the most prevalent primary liver disease occurring during pregnancy. Recent clinical and our preliminary studies have revealed that women with ICP and NAFLD have an increased risk for developing pregnancy complications of preterm birth (PTB) and stillbirth. However, the etiological link and underlying mechanisms remain to be determined. Currently there are limited intervention options to prevent or reduce pregnancy complications of PTB and stillbirth for pregnant women with liver diseases. In our recent and preliminary study with 36,755 pregnant women, we found that serum total bile acid (sTBA) levels directly correlate with the pregnancy complications of PTB and stillbirth and both ICP and NAFLD patients had markedly elevated sTBA levels. Bile acid cholic acid (CA) dose-dependently induced pregnancy complications of PTB and stillbirth and restoring bile acid homeostasis markedly reduced PTB and dramatically improved newborn survival rates. So, it was concluded that elevated bile acids are the etiological linker between liver diseases ICP and NAFLD and pregnancy complications of PTB and stillbirth. The overall objective of this proposal is to understand the mechanistic linkages among ICP, NAFLD, bile acids and pregnancy complications as well as the underlying mechanisms. The central hypothesis, built on our extensive preliminary results, is that elevated bile acids in pregnant women with liver disorders such as ICP and NAFLD induce pregnancy complications of PTB and stillbirth through activating the Takeda G protein-coupled receptor 5 (TGR5) signaling pathway, and restoring bile acid homeostasis by drugs will reduce or prevent bile acids-mediated pregnancy complications of PTB and stillbirth. Three specific aims will be conducted. Specific Aim 1 is to investigate the roles of TGR5 signaling pathway in the induction of pregnancy complications by elevated bile acids. Specific Aim 2 is to investigate increased risk and underlying mechanisms for NAFLD subjects to develop ICP and its associated pregnancy complications. Specific Aim 3 is to investigate the therapeutic potentials of four types of FDA-approved drugs that modulate bile acid homeostasis on pregnancy complications. The experiments proposed are built on our extensive, robust and novel preliminary findings, animal models established as well as our long- standing experience in studying bile acid regulation and associated liver diseases. our team is thus uniquely poised to investigate the underlying mechanisms and develop potential therapies for liver diseases-associated and bile acids-induced pregnancy complications of PTB and stillbirth.


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 = $393,664 )
2025	2025	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/14/2025	NON-COMPETING CONTINUATION	$39,365
2025	2025	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	$354,299
														Subtotal = $393,664

Issue Date FY: 2024 ( Subtotal = $390,924 )
2024	2024	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/26/2024	NEW	$390,924
														Subtotal = $390,924

Grand Total All Awards = $784,588

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Liver Diseases and Pregnancy Complications

Award Number: R01DK139489

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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