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Molecular mechanisms of T cell dysfunction in pediatric chronic cholestatic liver diseases

Award Number: K08DK141907
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/02/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Molecular mechanisms of T cell dysfunction in pediatric chronic cholestatic liver diseases - PROJECT SUMMARY/ABSTRACT This proposal details a comprehensive five-year training program investigating mechanisms of immune dysfunction in children with chronic cholestatic liver diseases (CSLD). These diseases are characterized by accumulation of bile acids in circulation and are the leading indication for liver transplantation (LT) in children. Infections cause significant morbidity and mortality in children with chronic liver diseases both pre-and post-LT. Dysregulated immune responses, which can be seen in cirrhosis associated immune dysfunction (CAID), represent a central driving force in infectious susceptibility and outcomes. However, the molecular basis of pediatric CAID remains unknown. Bile acids act as signaling molecules by binding to nuclear and cell surface receptors, playing a key role in immune regulation. Our preliminary studies, consistent with published reports, show that elevated levels of certain bile acids impair T cell proliferation in in vitro cultures. Further, preliminary studies from our pediatric cohort and mouse models show poor cytokine expression and impaired T cell proliferation in CSLD. Thus, our central hypothesis is that in children with chronic CSLD, bile acids act via the nuclear receptor VDR to transcriptionally repress genes involved in IFN-Ȗ SURGXFWLRQ OHDGLQJ WR LPSDLUHG 7 FHOO function, thereby causing pediatric CAID. To evaluate this hypothesis, we have formulated the following two distinct aims: (1) Determine the association between T cell functional deficits, viral infection and severity of cholestasis in children and in murine models of CSLD. (2) Determine the mechanism by which bile acids regulate T cell signaling in CSLD. I will use peripheral blood and plasma from children undergoing LT, two mouse models of cholestasis, and in vitro cell cultures with bile acids in these aims. Our expected outcome is to uncover new mechanisms of T cell dysfunction in cholestasis, which will ultimately lead to improved overall outcomes in CSLD. This work will be foundational to achieve my long-term goal of being an independent physician-scientist who develops therapies to mitigate the consequences of immune dysfunction in CSLD. The proposed experiments and didactic work will position me with a unique set of cross disciplinary skills that will enable my transition to independence as a physician scientist. I will be mentored by Dr. Benjamin Shneider, a leader in translational investigations of pediatric CSLD. I will be co-mentored by Dr. Farrah Kheradmand, an expert in the mechanisms of immune dysfunction in chronic diseases and Dr. Xian Li, a T cell biology expert. I will expand my translational research skills with training in T cell signaling, bile acid, and nuclear receptor biology. By leveraging integration of transcriptomic and metabolomic data using bioinformatic tools (Dr. Cristian Coarfa), I aim to gain a better understanding of immune deficits in CSLD and translate findings into improved patient care. This integrated approach is crucial for addressing clinical challenges associated with infections in children with liver disease. My training plan at a premiere academic research institution will provide knowledge and skills to make substantial contributions towards identifying and modifying risk factors of immune dysfunction in pediatric liver diseases.


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 = $167,165 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/6/2026	NEW	$167,165
														Subtotal = $167,165

Grand Total All Awards = $167,165

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Molecular mechanisms of T cell dysfunction in pediatric chronic cholestatic liver diseases

Award Number: K08DK141907

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/02/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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