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Principal Investigator: Zhenghui Gordon Jiang
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $686,264
Funding agency: National Institute on Alcohol Abuse and Alcoholism
SUMMARY
Alcohol-associated hepatitis (AH) is a form of subacute liver failure with high mortality, limited treatment
options, and elusive pathogenesis. Emerging evidence suggests that AH is associated with a profound
impairment in hepatocellular cholesterol homeostasis. Hepatocytes are the central hub for cholesterol
metabolism. Meanwhile, AH hepatocytes exhibit profoundly altered FC content and pathways responsible for
cholesterol esterification, transport, and conversion to bile acids. RNA sequencing studies indicate that the
dysregulation of HNF4α, a master hepatocyte transcription factor, is responsible for impaired cholesterol
homeostasis. Upregulation of HNF4α using small activating RNA (saRNA) could mitigate cholesterol toxicity in
vitro and can be developed as a treatment for AH.
Our long-term objective is to define the disease-centric pathways of AH and develop much-needed
therapeutics for AH patients. We hypothesize that the HNF4a-dependent impairment of cholesterol
homeostasis in hepatocytes directly contributes to hepatocellular dysfunction in AH and can be targeted
therapeutically. Our approach is to map regulatory pathways of cholesterol metabolism in human AH at a
single cell resolution, functionally interrogate cholesterol metabolic pathways in murine alcohol models, and
test a novel therapeutic strategy by targeting HNF4a-dependent cholesterol toxicity.
Aim 1 will map cholesterol metabolism in AH at single cell resolution using a multimodal approach. A three-
pronged strategy will map AH-associated changes in cholesterol homeostasis using single nuclear RNA
sequencing, ultra-high multiplexed imaging, and targeted spatial transcriptomics. The unbiased reference
maps will guide the interrogation of cholesterol metabolic pathways in cell and murine AH models.
Aim 2 will define the impact of cholesterol dysregulation on alcohol-induced liver injury in murine models.
We will model cholesterol toxicity in 3 conditions relevant to AH using the chronic-plus-binge alcohol feeding:
(1) acute cholesterol overload, (2) impaired bile acid synthesis, and (3) impaired cholesterol secretion in
cholestasis. This effort will generate optimized murine models that recapitulate cholesterol toxicity in AH.
Aim 3 will evaluate targeted manipulation of HNF4α-dependent pathways of cholesterol toxicity as a novel
therapeutic strategy in AH. We use saRNA to modulate HNF4α isoform expression and cholesterol
metabolism. GalNAc-conjugated HNF4α-saRNA will be tested as a hepatocyte-targeted therapeutics to
mitigate cholesterol toxicity in models of AH using differentiated human hepatocytes and murine models.
This project is built upon a strong team of multidisciplinary scientists combining unique expertise in
lipidology, preclinical liver models, and state-of-the-art single cell and spatial technologies. The success of this
project will further our understanding of AH pathogenesis and could lead to the development of a novel AH
treatment ready for preclinical and first-in-human trials.
Terms: <Acute><Acyltransferase><Alcohol Chemical Class><Alcohol associated hepatitis><Alcohol hepatitis><Alcohol induced hepatitis><Alcohol related hepatitis><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcohols><Atlases><Basal Transcription Factor><Basal transcription factor genes><Bile Acid Biosynthesis><Bile Acid Biosynthesis Pathway><Bile Acids><Bile Duct Obstruction><Biliary Stasis><Binding><Blood><Blood Reticuloendothelial System><CYP 7><CYP 7A><CYP7A><CYPVII><Cell Body><Cells><Cholestasis><Cholesterol><Cholesterol 7-alpha-Hydroxylase><Cholesterol 7-alpha-Monooxygenase><Cholesterol 7alpha-Hydroxylase><Cholesterol Homeostasis><Cholesterol-7-Hydroxylase><Choline Glycerophospholipids><Choline Phosphoglycerides><Chronic><Cytochrome P-450 CYP7><Cytochrome P450 7><Cytochrome P450 7A1><Cytochrome P450 Family 7 Subfamily A Polypeptide 1><Development><Disease><Disorder><Dysfunction><EC 2.3><Enzyme Gene><Enzymes><Esterification><Ethanol-induced hepatitis><Exhibits><Experimental Models><Functional disorder><General Transcription Factor Gene><General Transcription Factors><HNF4><HNF4-Alpha><HNF4A><HNF4A gene><Hepatic Cells><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatitis><Hepatocyte><Hepatocyte Nuclear Factor 4-Alpha><Hepatocyte Nuclear Factor, 4><Hepatotoxic effect><Hepatotoxicity><Human><Impairment><In Vitro><Individual><Isoforms><Knowledge><Lecithin><Link><Lipoproteins><Liver><Liver Cells><Liver Failure><Liver Toxicity><Liver diseases><Maps><Messenger RNA><Metabolic Pathway><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Non-Polyadenylated RNA><Nuclear RNA><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Phosphatidylcholines><Physiopathology><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Prebeta-Lipoproteins><Production><Protein Isoforms><Proteins><RNA><RNA Gene Products><RNA Interference><RNA Seq><RNA Silencing><RNA sequencing><RNAi><RNAseq><Regulatory Pathway><Resolution><Ribonucleic Acid><Route><Sampling><Scientist><Sequence-Specific Posttranscriptional Gene Silencing><Single-Nucleus Sequencing><TCF14><Technology><Testing><Therapeutic><Toxic effect><Toxic effect on liver cells><Toxicities><Transcription Factor 14, Hepatic Nuclear Factor><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Model><Transportation><Treatment Efficacy><Up-Regulation><Upregulation><VLDL><VLDL Lipoproteins><Very low density lipoprotein><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol related liver disease><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic liver injury><bile acid anabolism><bile acid biosynthetic process><bile acid formation><bile acid synthesis><bile obstruction><bile occlusion><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><cholesterol metabolism><developmental><disease model><disorder model><efficacy testing><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><feeding><first in man><first-in-human><hepatic body system><hepatic disease><hepatic organ system><hepatic toxicity><hepatocyte nuclear factor><hepatopathy><hepatoxicity><in vivo><intervention efficacy><liver disorder><mRNA><mortality><mouse model><multi-modality><multidisciplinary><multimodality><multiplexed imaging><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pathway><pre-clinical><preclinical><predict clinical outcome><resolutions><reverse cholesterol transport><sNuc-Seq><screening><screenings><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic target><therapy efficacy><tool><transcription factor><transcriptome sequencing><transcriptomic sequencing><transcriptomics><transgenic trait><treatment strategy><uptake>