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Injury, Progression, and Fibrosis of the Extrahepatic Bile Duct

Award Number: R01DK119290
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: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Injury, Progression, and Fibrosis of the Extrahepatic Bile Duct - PROJECT SUMMARY The goal of this proposal is to determine the role of fetal vs. adult wound healing programs – and the switch from one to the other that occurs around birth – in the response to fetal/early neonatal extrahepatic bile duct injury, such as occurs in biliary atresia (BA). BA is a rare disease occurring worldwide that it is thought to occur from a prenatal environmental insult – affecting only the fetus – to the extrahepatic bile duct (EHBD). Babies appear healthy at birth, but undergo rapid progression of the disease to fibrosis and obstruction of the duct and cirrhosis of the liver. There are three major unanswered questions that motivate this proposal:  Why does an EHBD insult during pregnancy affect only the fetus?  Do some babies with fetal EHBD injury recover, and if yes, why recovery rather than fibrosis?  Why does the disease progress so rapidly after birth? Our preliminary data suggest that prenatal EHBD injury leads to a program of fetal wound healing in the initial response of the fetal EHBD to injury. Fetal wound healing, which has been reported in multiple tissues, results in regeneration rather than scarring and is particularly notable for the deposition of high molecular weight hyaluronic acid (HA) rather than type I collagen, with a growth factor milieu that includes IL-10 rather than TGF-. The switch from a fetal to an adult wound healing program occurs late in gestation. We hypothesize that fetal and adult wound healing programs, in sequence, determine the response to fetal EHBD injury; that both have the potential to enhance damage and injury progression; and that co-opting these responses would have a major therapeutic benefit. We propose to test these hypotheses through 2 specific aims that study wound healing in sequence from the fetus to the newborn, including the impact of natal stress on the transitional program between fetal and adult: 1) Define the nature of fetal wound healing and its impact on the injury response in the fetal EHBD; and 2) Determine the impact of birth-associated stress and the switch to an adult wound healing program in the context of an HA-laden EHBD after the events of fetal wound healing. The proposed work introduces a new concept – fetal wound healing – to the study of BA. Understanding fetal wound healing in BA, both its positive and negative effects, will be essential in the development of potentially transformative treatments.


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 = $357,500 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/8/2026	NON-COMPETING CONTINUATION	$357,500
														Subtotal = $357,500

Issue Date FY: 2025 ( Subtotal = $357,500 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	8/29/2025	NON-COMPETING CONTINUATION	$357,500
														Subtotal = $357,500

Issue Date FY: 2024 ( Subtotal = $343,200 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	5/10/2024	NON-COMPETING CONTINUATION	$343,200
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	5/3/2024	COMPETING CONTINUATION	$0
2024	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,200

Issue Date FY: 2023 ( Subtotal = $357,500 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/7/2023	COMPETING CONTINUATION	$357,500
														Subtotal = $357,500

Issue Date FY: 2022 ( Subtotal = $365,625 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/10/2022	NON-COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2021 ( Subtotal = $365,625 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/24/2021	NON-COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2020 ( Subtotal = $364,500 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/23/2020	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $364,500

Issue Date FY: 2019 ( Subtotal = $364,500 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/30/2019	NEW	$364,500
														Subtotal = $364,500

Grand Total All Awards = $2,875,950

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Injury, Progression, and Fibrosis of the Extrahepatic Bile Duct

Award Number: R01DK119290

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: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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