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The Unfolded Protein Response in Murine and Pediatric Cholestatic Liver Diseases

Award Number: K08DK132456
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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The Unfolded Protein Response in Murine and Pediatric Cholestatic Liver Diseases - Cholestatic liver diseases, including biliary atresia (BA), are the leading indication for pediatric liver transplant and there are no effective medical therapies for patients that decrease the need for transplantation. This is due, in part, to the lack of understanding of how the liver reacts to bile acid induced injury in children, including the hepatocyte activation of the unfolded protein response (UPR). The UPR is a protective molecular response that decreases endoplasmic reticulum (ER) stress which can occur in the setting of cholestasis, in part through induction of ER-associated degradation (ERAD) pathways. Our laboratory’s previously published and present preliminary data using several models of ER stress demonstrate that young mice have inadequate UPR activation (specifically within the XBP1 pathway) compared to adult mice, and this is associated with increased liver injury. The same pattern of impaired XBP1 pathway activation occurs in explanted livers from pediatric patients with cholestatic liver diseases compared to both normal and disease controls. The goal of my current investigations is to increase the understanding of the pathophysiologic hepatic responses of the XBP1 pathway to cholestatic liver injury and identify changes during postnatal development that influence UPR activation. This will allow us to target specific UPR pathways for the development of novel treatments for pediatric cholestatic liver diseases. Therefore, I have formulated the following Specific Aims: 1) To define age-dependent changes in XBP1 transcription factor function using murine models of ER stress 2) To define the protective mechanism of XBP1 regulation of ERAD in chronic cholestasis and 3) To determine the changes in mechanism of XBP1 signaling which occur in murine and human biliary atresia (BA). Using murine models of ER stress and cholestasis and human liver tissue from BA patients we will identify the mechanism of XBP1 specific pathway changes that occur during post-natal development, and how these changes influence disease progression in response to cholestasis-induced ER stress. Candidate and Career Development: I am a pediatric hepatologist at Northwestern University who has a demonstrated commitment to basic/translational research throughout my early career. My long-term career goal is to become an independent, extramurally funded physician-scientist with a focus on the hepatocellular UPR response in pediatric cholestatic liver diseases. This K08 proposal will help achieve this goal by advancing my scientific skills and knowledge in gene regulation, cellular signaling pathway analysis and high-throughput data analysis, as well as defining the role of the unfolded protein response in murine cholestatic liver disease models and correlative human diseases. Along with my co-mentors, Drs. Green and Barish, I have developed a career development plan to achieve these goals through didactic lectures, mentoring, and hands-on laboratory training. This proposal will provide the protected time and research training for future R01-level proposals extending mechanistic XBP1 pathway studies within pediatric cholestatic liver diseases and investigating UPR-related therapeutics.


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 = $163,012 )
2026	2026	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/26/2026	NON-COMPETING CONTINUATION	$163,012
														Subtotal = $163,012

Issue Date FY: 2025 ( Subtotal = $162,920 )
2025	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/9/2025	NON-COMPETING CONTINUATION	$162,920
														Subtotal = $162,920

Issue Date FY: 2024 ( Subtotal = $164,452 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/15/2024	NEW	$164,452
														Subtotal = $164,452

Grand Total All Awards = $490,384

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The Unfolded Protein Response in Murine and Pediatric Cholestatic Liver Diseases

Award Number: K08DK132456

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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