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Molecular Mechanism of Sickle Cell Hepatic Crisis

Award Number: K01DK125617
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/15/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Molecular Mechanism of Sickle Cell Hepatic Crisis - Project Summary/Abstract The goal of this proposal is to extend my training as an independent scientist in the field of hepatic manifestations of Sickle cell disease (SCD). To this end, I have selected the division of Hematology-Oncology at University of Pittsburgh to continue my transition to become an independent investigator at an academic institution. This proposal outlines an extensive Research Strategy that is complemented by several areas of training, which includes several courses directly related to my studies in Specific Aims, meeting with my junior faculty research committee, and attendance and participation of multiple seminars throughout the University Of Pittsburgh Medical School. My Research Strategy will determine the molecular mechanisms of SCD induced hepatic crisis. SCD is an autosomal-recessive monogenic disorder that affects approximately 100,000 Americans and millions of people worldwide. Sinusoidal vaso-occlusion and hemolysis are considered as chief contributors of sickle hepatic crisis. Hepatic crisis affects 10-40% of hospitalized SCD patients which is characterized by liver injury and sickle cell intrahepatic cholestasis (SCIC) that can progress to fatal liver failure. The current treatment for hepatic crisis is primarily supportive, and the molecular mechanism is unknown, suggesting that preventive therapies based on the improved understanding of the molecular pathways that enable SCIC are needed. In this study, we have used a transgenic, humanized mouse model of SCD that exclusively expresses sickle human hemoglobin. Preliminary findings reveal that SCD mice developed chronic liver injury with age, which was manifested by sustained inflammation, hyperbilirubinemia and cholestasis. Using our recently developed real-time in vivo imaging of the intact liver of live mice, we discovered the presence of sinusoidal ischemia and impaired bile transport across the apical membrane of hepatocytes in SCD mice. The impaired bile transport was associated with loss of apical bile transporters (BSEP, ABCG5 and ABCG8) from hepatocytes. RNA-seq analysis identified dysregulation of genes encoding proteins responsible for inflammation and bile secretion in the liver of SCD mice. Furthermore, we observed NF-κB activation in the liver of SCD mice inhibited FXR signaling and its downstream targets, leading to impaired bile secretion. These findings form the basis for my overarching hypothesis that ischemia and hemolysis induced inflammation, tissue injury and oxidative stress promotes NF-kB activation in sickle hepatocytes which inhibits FXR signaling leading to impaired bile secretion in SCD, and activating FXR or rescuing bile secretion can ameliorate SCIC. This hypothesis will be tested in the following aims: 1) To determine whether ischemia-reperfusion injury and hemolysis promotes hepatocyte specific activation of NF-kB in SCD and 2) To determine whether hepatocyte-specific activation of NF-kB promotes loss of FXR-signaling leading to impaired bile secretion and cholestasis in SCD. The successful completion of this NIH-K01 training award will set the stage for an RO1 proposal aimed at elucidating how the manipulation of inflammatory pathways, FXR signalling and bile secretion can rescue SCIC and progressive liver injury in SCD.


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 = $0 )
2025	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$608
2025	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/25/2025	NON-COMPETING CONTINUATION	-$608
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $147,139 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	5/28/2024	NON-COMPETING CONTINUATION	$147,139
2024	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$74,830
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/12/2024	NON-COMPETING CONTINUATION	-$74,830
														Subtotal = $147,139

Issue Date FY: 2023 ( Subtotal = $146,899 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/26/2023	NON-COMPETING CONTINUATION	$146,899
														Subtotal = $146,899

Issue Date FY: 2022 ( Subtotal = $146,899 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/28/2022	NON-COMPETING CONTINUATION	$146,899
														Subtotal = $146,899

Issue Date FY: 2021 ( Subtotal = $146,899 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/15/2021	NON-COMPETING CONTINUATION	$146,899
														Subtotal = $146,899

Issue Date FY: 2020 ( Subtotal = $148,399 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/7/2020	NEW	$148,399
														Subtotal = $148,399

Grand Total All Awards = $736,235

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Molecular Mechanism of Sickle Cell Hepatic Crisis

Award Number: K01DK125617

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/15/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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