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Mechanisms of neutrophil extracellular trap formation and contribution to biliary fibrosis in biliary atresia

Award Number: R01DK140072
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: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Mechanisms of neutrophil extracellular trap formation and contribution to biliary fibrosis in biliary atresia - PROJECT SUMMARY/ABSTRACT Biliary atresia (BA) is an inflammatory, sclerosing lesion of the biliary tree that presents in infancy and is associated with significant biliary fibrosis. The degree of fibrosis at presentation is unprecedented compared to any other organ-specific disease of infancy and the vast majority of BA patients will need liver transplantation for survival. Various immune pathways have been implicated in cholangiocyte injury in BA, yet key immune pathways that promote fibrosis are unknown. A critical barrier to discovering novel therapies in BA is the lack of an understanding of key cellular mechanisms promoting biliary fibrosis. The biomarker CXCL8 (IL-8), a neutrophil chemoattractant and activator, and neutrophil extracellular traps (NETs) have been previously shown to predict worse outcomes in BA. Significant preliminary data within this proposal reveals that neutrophils are chronically activated in BA patients, with persistent CXCL8-CXCR2-mediated NET formation (NETosis). Constituents of BA NETs include pro-fibrogenic proteins and NETs positively correlate with biomarkers of injury and fibrosis. The hypothesis to be tested is that the immunopathogenesis of BA involves CXCL8-CXCR2-mediated NETosis, resulting in NET-induced portal fibroblast and stellate cell activation. The rotavirus-induced mouse model of BA (murine BA), as well as analyses of human biospecimens, will be employed to address the hypothesis. Specific Aim 1 will determine if neutrophil CXCR2 activation is essential for NETosis in murine BA. Specific Aim 2 will determine the predominant source of reactive oxygen species that is necessary for NETosis (NADPH-oxidase dependent versus mitochondrial source). Specific Aim 3 will establish the pro-fibrogenic role of NETs in BA, including portal fibroblast and hepatic stellate cell activation through use of primary cell lines and hepatic organoids. Impact. Discoveries from this research could be highly impactful, with increased knowledge gained in neutrophil biology and with the identification of novel therapeutics targeting NETosis that would prevent biliary cirrhosis in children with BA.


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 = $545,972 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/15/2025	NON-COMPETING CONTINUATION	$545,972
														Subtotal = $545,972

Issue Date FY: 2024 ( Subtotal = $545,972 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/19/2024	NEW	$545,972
														Subtotal = $545,972

Grand Total All Awards = $1,091,944

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Mechanisms of neutrophil extracellular trap formation and contribution to biliary fibrosis in biliary atresia

Award Number: R01DK140072

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: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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