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Principal Investigator: Aras Nikodemas Mattis
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $669,949
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
This is a research grant application for a study being undertaken in the laboratory of Dr. Aras Mattis, a
Scientist at the University of California, San Francisco (UCSF). This grant will provide support for the Mattis lab
to conduct this research over the five-year term of this project.
Differentiation of patient induced pluripotent stem cells (iPSCs) to hepatocytes (iPSC-Heps) has
incredible value for modeling and experimental treatment of human hepatic disease. My lab has significant
expertise in the differentiation of iPSCs to human hepatocytes and therefore modeling of liver diseases. The
major goal of this project is to use iPSC-Hep cell lines that we have developed from a single family of patients
with NASH and matched controls to study modeling of NAFLD in vitro and the relationship of novel genes we
uncovered to the disease process. First, we will use the iPSC-Hep model to test a set of genes with unknown
function for involvement in NAFLD. We uncovered these genes by sequencing this family with severe and
penetrant NASH. Furthermore, we will test loss of function knockouts of these novel genes in control iPSC-
Heps, for their ability to cause steatosis, endoplasmic reticulum (ER) stress, and/or inflammatory pathway
activation. Finally we will test a set of genes we uncovered as potentially therapeutic targets.
The specific experimental aims of this project are to 1) Identify NAFLD pathways modeled in patient
7017 familial NASH iPSC-Heps, 2) Establish contribution of known SNPs and novel genes for involvement in
NAFLD Phenotypes, and 3) Test our previously identified genes as therapeutic targets in 7017 iPSC-Heps.
This project follows the mission of the NIH to support medical research on hepatic diseases with the potential
for clinical translational use.
Terms: <Affect><Apopain><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 3><Applications Grants><Assay><Bioassay><Biological Assay><Body Tissues><CASP-3><CASP3><CASP3 gene><CPP-32><CPP32><CPP32 protein><CPP32B><CPP32beta><CRISPR approach><CRISPR based approach><CRISPR interference><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR-dCas9-mediated repression><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><California><Cas nuclease technology><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cirrhosis><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats interference><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Cysteine Protease CPP32><Cysteine Protease CPP32 Gene><Development><Diet><Disease><Disease Pathway><Disorder><Dose><Doxycycline><ER stress><Environment><Family><Fibrosis><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Grant Proposals><Health><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Hexadecanoates><Human><Human Engineering><Immunoblotting><In Vitro><Inflammasome><Inflammatory><Insulin Resistance><Intracellular Accumulation of Lipids><Intracellular Communication and Signaling><JNK-55><JNK2><JNK2 Kinase><JNK2 Stress-Activated Protein Kinase><JNK2A><JNK2Alpha><JNK2B><JNK2Beta><Kinetics><Knock-out><Knockout><Laboratories><Life><Lipids><Liver><Liver Cells><Liver Cells Carcinoma><Liver diseases><MAPK9><MAPK9 Mitogen-Activated Protein Kinase><MAPK9 gene><Manuscripts><Measures><Medical Research><Methods><Mission><Mitogen-Activated Protein Kinase 9><Modeling><Modern Man><Mutation><NAFLD><NASH><NIH><National Institutes of Health><Obesity Epidemic><Oleates><Oxidative Stress><PARP Cleavage Protease><PARP Cleavage Protease Gene><PRKM9><Palmitates><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Phenotype><Phosphorylation><Population><Predisposition><Preparation><Primary carcinoma of the liver cells><Process><Programmed Cell Death><Proliferating><Protein Phosphorylation><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Seq><RNA Splicing><RNA sequencing><RNAseq><Research><Research Grants><Research Project Grants><Research Projects><Risk><SCA-1><SCA-1 Gene><SREBP Cleavage Activity 1><SREBP Cleavage Activity 1 Gene><San Francisco><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Splicing><Strains Cell Lines><Study models><Susceptibility><System><Testing><Tissues><Titrations><United States National Institutes of Health><Universities><Variant><Variation><Vibramycin><Western Blotting><Western Immunoblotting><XBP1><XBP1 gene><Yama><Yama protein><alpha-6-Deoxyoxytetracycline><biological adaptation to stress><biological signal transduction><burden of disease><burden of illness><c-jun Kinase-2><caspase-3><cirrhotic><clinical translation><clinically translatable><cultured cell line><cysteine protease P32><cytokine><developmental><diets><disability><disease burden><disease model><disease phenotype><disorder model><endoplasmic reticulum stress><exome sequencing><exome-seq><exosome><experiment><experimental research><experimental study><experiments><gain of function><genome mutation><hepatic body system><hepatic disease><hepatic inflammation><hepatic organ system><hepatopathy><iPS><iPSC><iPSCs><in vitro Model><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><inflamed liver><insulin resistant><insulin tolerance><intrahepatic><liver carcinoma><liver disorder><liver inflammation><loss of function><mouse model><murine model><mutant><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><p54aSAPK><pathway><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><preparations><protein blotting><reaction; crisis><repair><repaired><repressing CRISPR-dCas9 system><single nucleotide variant><stress response><stress; reaction><therapeutic agent development><therapeutic development><therapeutic target><transcriptome sequencing><transcriptomic sequencing><vector>