# Molecular mechanism of Sickle Cell Hepatic Crisis

> **NIH NIH K01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $148,399

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10038866
- **Project number:** 1K01DK125617-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Tirthadipa Pradhan-Sundd
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $148,399
- **Award type:** 1
- **Project period:** 2020-07-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10038866

## Citation

> US National Institutes of Health, RePORTER application 10038866, Molecular mechanism of Sickle Cell Hepatic Crisis (1K01DK125617-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10038866. Licensed CC0.

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