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Principal Investigator: Alexis Noel Ross
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2020
Award: $29,520
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
The mechanisms that control hepatic stellate cell (HSC) migration during liver development and
regeneration are not well understood. This knowledge gap has hindered the generation of new therapies and
the improvement of patient outcome for various developmental disorders such as congenital hepatic fibrosis and
fibrosing liver diseases such as alcoholic and non-alcoholic steatohepatitis. The critical need addressed in this
proposal is to identify and characterize factors that influence HSC migration during development and in
regeneration. HSCs migrate to the liver from the septum transversum early in vertebrate development. Once in
the liver, HSCs secrete growth factors and cytokines, such as TGF-ß and FGF10, that promote hepatocyte
proliferation. In the healthy adult liver, HSCs’ main function is to act as a storage site for vitamin A and regulate
extracellular matrix (ECM) turnover. When the liver is injured, HSCs migrate to the liver injury site where they
secrete ECM, growth factors, and cytokines to promote liver regeneration. Little is known about the factors
involved in HSC migration into the liver during development and throughout the liver in response to injury. My
long-term goal is to define mechanisms of liver development and regeneration, providing a foundation for
improved therapies and patient outcomes for congenital disorders and fibrotic liver diseases. The overall
objective of this proposal is to define mechanisms that control HSC behavior during development and
regeneration. The central hypothesis in this proposal is that podxl regulates HSC migration to the liver during
normal development (Aim 1), and within the liver in response to injury (Aim 2). Podxl is a highly sialylated and
glycosylated transmembrane protein that is known to promote migration of several cell types, including
hematopoietic stem cells and cancer cells. Several studies have shown that podxl is highly expressed in
zebrafish HSCs, and our preliminary data demonstrates that knockdown of podxl in zebrafish during
development results in fewer HSCs in the liver. In this study, the aim is to determine the role of podxl in HSCs
during development and regeneration. A podxl mutant and overexpression line will be created to determine the
role and mechanism of podxl in development. The working hypothesis is that Podxl promotes HSC migration by
interaction of its DTHL motif with the actin-binding protein Moesin. In addition, homologous recombination will
be used to create an HSC-specific Cre line that can be used to knock down genes in HSCs. This new HSC
expressing Cre line will be used to knock down podxl in HSCs and determine how that influences their migration
to liver injury sites and subsequent hepatocyte proliferation. This project involves generating novel genetic and
imaging tools, which will be instrumental for my career development. Understanding the role of podxl in HSC
migration during development and regeneration is significant because it will provide a foundation for generating
new treatments for chronic liver diseases.
Terms: <21+ years old><Abscission><Actin-Binding Protein><Actins><Address><Adhesions><Adult><Adult Human><Alcoholic><Area><Biologic Models><Biological Models><Blood Precursor Cell><Bone-Derived Transforming Growth Factor><Boozer><Brachydanio rerio><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Count><Cell Locomotion><Cell Migration><Cell Movement><Cell Number><Cell-Extracellular Matrix><Cellular Migration><Cellular Motility><Cicatrix><Cirrhosis><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><Congenital Disorders><Danio rerio><Data><Dependent drinker><Development><Drugs><ECM><Environment><Excision><Extirpation><Extracellular Matrix><FGF-10><FGF10><FGF10 gene><Fibrosis><Foundations><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Growth Agents><Growth Factor><Growth Substances><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatic Transplantation><Hepatocyte><Human><Imaging Device><Imaging Instrument><Imaging Tool><Injury><Injury to Liver><Integral Membrane Protein><Intrinsic Membrane Protein><Ito Cell><Kidney><Kidney Urinary System><Knock-out><Knockout><Knowledge><Larva><Lead><Lipids><Liver><Liver Cells><Liver Fibrosis><Liver Grafting><Liver Regeneration><Liver Transplant><Liver diseases><Location><Malignant Cell><Mediating><Medication><Mice><Mice Mammals><Milk Growth Factor><Model System><Modern Man><Morphology><Motility><Murine><Mus><Mutate><Mutation><NASH><Natural regeneration><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Platelet Transforming Growth Factor><Play><Protein Family><Proteins><Proteins Growth Factors><Recovery><Regeneration><Removal><Role><Scars><Septum Transversum><Site><Structure of septum transversum><Surgical Removal><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Toxin><Transcript Expression Analyses><Transcript Expression Analysis><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transgenic Organisms><Transmembrane Protein><Transmembrane Protein Gene><Vitamin A><Zebra Danio><Zebra Fish><Zebrafish><adulthood><base><blood stem cell><cancer cell><career development><cell behavior><cell motility><cell type><cellular behavior><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><cirrhotic><cytokine><developmental><developmental disease><developmental disorder><drug/agent><ezrin><fibroblast growth factor 10><fibrotic liver><gene expression analysis><gene expression assay><genome mutation><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><hepatic body system><hepatic cell proliferation><hepatic cellular proliferation><hepatic damage><hepatic disease><hepatic fibrosis><hepatic injury><hepatic organ system><hepatocyte cell proliferation><hepatocyte cellular proliferation><hepatocyte injury><hepatocyte proliferation><hepatopathy><homologous recombination><imaging in vivo><improved><in vivo imaging><injured><injuries><injury response><invention><knock-down><knockdown><liver cell proliferation><liver cellular proliferation><liver damage><liver development><liver disorder><liver injury><liver transplantation><membrane-organizing extension spike protein><migration><moesin><mutant><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><non-alcohol induced steatohepatitis><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><overexpress><overexpression><phosphoprotein p81><podocalyxin><polymerization><problem drinker><radixin><radixin protein><regenerate><renal><resection><response><response to injury><social role><therapeutic outcome><therapy outcome><tool><transcriptional profiling><transgenic>