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NIH grant 1F30AA033246-01: The circRNA-Sphingolipid Axis: A Novel Driver of Alcohol-Associated Liver Disease.
Institute: {'code': 'AA', 'abbreviation': 'NIAAA', 'name': 'National Institute on Alcohol Abuse and Alcoholism', 'admin_org_id': '12500001', 'admin_funding_url': ''}. PI: Hongkun Lu. Award: $45406.
Start: 2026-07-25T00:00:00.
PROJECT SUMMARY/ABSTRACT
Alcohol associated liver disease (ALD) is a prevalent and debilitating liver disease worldwide that contributes to
cirrhosis and liver failure, and there are currently no drugs or treatment for ALD. Sphingolipids have been
implicated in the pathogenesis of metabolic diseases, particularly through their roles in inflammation. However,
the role of sphingolipid metabolism in ALD remains poorly understood. Preliminary data indicates that the
glycosphingolipid synthesis pathway, along with key metabolic genes such as UDP Glucose Ceramide
Glucosyltransferase (UGCG) and UDP glycosyltransferase 8 (UGT8) are significantly upregulated in patients
with ALD. Despite these findings, the precise role of glycosphingolipids in alcohol-induced liver injury and the
mechanisms driving ALD progression have not been characterized. Circular RNAs (circRNA), a class of non-
coding RNAs characterized by their covalently closed structure, have been shown to regulate gene expression
by interacting with microRNAs (miRNAs) and RNA binding proteins (RBPs). Preliminary data identified that
circUGCG, a circRNA derived from UGCG, was significantly upregulated in ALD patients, suggesting a novel link
between the glycosphingolipid pathway and circular RNAs in ALD pathogenesis. The overall objective of this
project is to elucidate the roles and mechanisms in which circUGCG contribute to ALD, and the ultimate goal is
to identify targets for diagnostic tools and therapeutic development. Based on the hypothesis that elevated
expression of circUGCG promotes ALD pathogenesis by disrupting sphingolipid homeostasis and exacerbating
hepatocellular injury and inflammation, the following aims are proposed: Aim 1. Examine the role of circUGCG
in alcohol-induced hepatic injury and inflammation using targeted genetic approaches in in vitro and ex vivo
models. Using RNA biology experiments, organoids, and RNA sequencing, the proposed project will define the
contribution of circUGCG to these pathological processes. Aim 2. Identify the cellular/molecular mechanisms
and pathways by which circUGCG induces sphingolipid dysregulation and liver injury in ALD. The proposed
project will investigate the potential mechanisms by which the dysregulated circRNA-sphingolipid axis
contributes to the progression of ALD via circRNA-miRNA-mRNA networks and circRNA-RBP interactions using
sphingolipidomics, ALD mouse models, spatial transcriptomics, and RNAscope. Accomplishing these aims could
provide valuable information for the development of new therapeutics and biomarkers. Further, this application
includes an excellent research environment for the proposed work, including a collaborative mentorship team of
physician scientists and scientists, access to cutting edge technologies and resources, and multiple well-funded
and supportive Institutes and Centers that encourage translational research. The candidate will resultantly learn
new scientific skills, gain knowledge and skills in basic science, clinical trials, and translational research, and
participate in professional development. This training is critical towards the candidate’s goals of becoming an
independent physician scientist, performing translational research, and treating patients as a gastroenterologist.document fetched 2026-08-02 08:24