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Principal Investigator: Jiandie D Lin
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $510,001
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
The obesity epidemic has increased the prevalence of non-alcoholic fatty liver disease, which ranges from
clinically benign hepatic steatosis to non-alcoholic steatohepatitis (NASH). The latter represents a more severe
disease state featured by the presence of chronic liver injury, inflammation, and liver fibrosis, which increases
the risk for end-stage liver disease such as cirrhosis and hepatocellular carcinoma (HCC). Macrophages play
an integral role in host defense, tissue homeostasis, and disease progression. Altered macrophage
polarization, characterized by changes in its transcriptional and functional states, has been causally linked to
the pathogenesis of metabolic disease including NASH. Despite this, the nature of macrophage heterogeneity,
disease-associated reprogramming, and its contribution to NASH progression remains obscure. To address
these challenges, we recently performed single-cell RNA sequencing analysis on liver cells isolated from
healthy and diet-induced NASH mice. Our study uncovered a unique population of NASH-associated
macrophages (NAMs) that exhibits strong association with mouse and human NASH. Several important
questions emerge from these findings regarding the pathophysiological signals that trigger NAM induction, its
role in NASH pathogenesis, and the underlying mechanisms. Based on a body of preliminary data, we
hypothesize that intrahepatic pathogenic stimuli drive NAM induction during NASH, thereby reshaping the liver
microenvironment and exacerbating disease progression. In this proposal, we plan to elucidate the signaling
pathways that promote NAM induction and critically assess its role in disease pathogenesis. We plan to
explore the mechanisms through which NAMs contribute to the reprogramming of the liver microenvironment.
Terms: <ACVRLK4><Ablation><Address><Adopted><Adult-Onset Diabetes Mellitus><Autoregulation><Benign><Biology><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Calcium><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cirrhosis><Clinical><Data><Development><Development Plans><Diet><Dimensions><Disease><Disease Progression><Disorder><Exhibits><Fatty Liver><Fibrosis><Foundations><Future><Gene Transcription><Genetic><Genetic Models><Genetic Transcription><Hepatic Cancer><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Heterogeneity><Homeostasis><Host Defense><Human><Inflammasome><Inflammation><Injury><Insulin Resistance><Intracellular Communication and Signaling><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-in><Knock-out Mice><Knockout Mice><Knowledge><Link><Lipids><Liver><Liver Cells><Liver Cells Carcinoma><Liver Fibrosis><Liver Steatosis><Macrophage><Malignant neoplasm of liver><Maturity-Onset Diabetes Mellitus><Mediating><Membrane><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Myelogenous><Myeloid><Mφ><NAFLD><NASH><NIDDM><Nature><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Obesity Epidemic><Pathogenesis><Pathogenicity><Pathology><Pathway interactions><Pattern><Physiological Homeostasis><Play><Population><Prevalence><Primary carcinoma of the liver cells><Public Health><RNA Expression><Regulation><Risk><Role><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stimulus><T2 DM><T2D><T2DM><TGFBR1><TGFBR1 gene><TREM2><TREM2 gene><Therapeutic><Thesaurismosis><Tissues><Transcription><Transgenic Organisms><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><U-PA><U-Plasminogen Activator><Urinary Plasminogen Activator><Urokinase><Urokinase Plasminogen Activator><Urokinase-Type Plasminogen Activator><adult onset diabetes><biological signal transduction><cancer microenvironment><cell sorting><cell type><chronic liver injury><cirrhotic><conditional knock-out><conditional knockout><design><designing><developmental><dietary><diets><disease model><disorder model><effective therapy><effective treatment><end stage liver disease><end stage liver failure><fibrotic liver><gene signatures><genetic signature><genomic tools><global gene expression><global transcription profile><hepatic body system><hepatic fibrosis><hepatic organ system><hepatic steatosis><hepatosteatosis><injuries><insight><insulin resistant><insulin tolerance><intrahepatic><ketosis resistant diabetes><knockin><liver cancer><liver carcinoma><liver malignancy><malignant liver tumor><maturity onset diabetes><membrane structure><metabolism disorder><non-alcohol fatty liver disease><non-alcohol induced steatohepatitis><non-alcoholic fatty liver disease><non-alcoholic liver disease><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcoholic fatty liver disease><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel><pathway><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><tool><transcriptome><transcriptomics><transgenic><translational study><tumor microenvironment><type 2 DM><type II DM><type two diabetes>