Yi Guo, Ph.D., conducts basic biomedical research, seeking to understand the molecular and cellular basis of neutral-lipid storage-related metabolic disease, such as obesity, diabetes and nonalcoholic fatty liver disease (NAFLD).
Dr. Guo's research focuses on understanding intracellular lipid storage and mobilization in specialized cellular organelles called lipid droplets, function of lipids and lipid metabolites in lipotoxicity and cell death.
Her approaches combine the power of gene discovery through reverse genetic screening, protein functional characterization via biochemistry studies, detailed cell biological characterization employing the toolboxes of molecular imaging, and physiological investigation based on genome engineering using in vivo models.
Lipotoxicity in human liver cells. With support from the Mayo Clinic Center for Biomedical Discovery, Dr. Guo and collaborators are using the newly developed EXPAND human lentivirus shRNA library to discover novel mediators for lipotoxicity in human liver cells (hepatocytes). This unique, unbiased, genome-wide RNA interference (RNAi) screen identifies new players in NAFLD for further cell biological investigation and translational research.
This multidisciplinary project is in close collaboration with Mayo Clinic researchers Gregory J. Gores, M.D., and Harmeet Malhi, M.B.B.S., in the Division of Gastroenterology and Hepatology, Taofic Mounajjed, M.D., in the Department of Laboratory Medicine and Pathology, and Jan van Deursen, Ph.D., in the departments of Pediatric and Adolescent Medicine and of Biochemistry and Molecular Biology, and with Michael T. McManus, Ph.D., in the Diabetes Center at University of California, San Francisco.
Genome engineering in Drosophila melanogaster. Previously, Dr. Guo and colleagues established the effective and powerful platforms of genome engineering — transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR) — in the model organism Drosophila melanogaster.
These technology advancements are novel additions to the fly geneticist's toolbox, for easier and routine genomic engineering applications. They are actively using this technology to model human diseases, especially in the area of human hepatocellular carcinoma research.
Lipid-droplet biology. Additionally, Dr. Guo carried out the first comprehensive functional genomic study toward mapping the genetic landscape that shapes lipid-droplet biology. Lipid droplets are the cellular hubs for energy storage and the center organelles to target for understanding mechanism of metabolic diseases. Yet very little is known about how this organelle forms, grows and mobilizes.
Using drosophila S2 cells, Dr. Guo's team finished a genome-wide RNAi screen looking for genes affecting lipid droplets in this cell line. The completion of this study led to the identification of several classes of genes that affect lipid droplets within cells. These include the vesicular trafficking machinery and the phospholipid metabolism genes. Understanding these processes in vitro and in vivo may provide new therapeutic targets to reverse the excess lipid storage in obese tissues.
Significance to patient care
Dr. Guo's long-term research goal is to apply the basic molecular mechanisms gained to develop effective prevention and therapeutics for diet-induced obesity, diabetes and NAFLD.