Qisheng Zhang Laboratory
Qisheng Zhang Laboratory
Our lab studies lipid signaling pathways that are involved in development and diseases by developing novel chemical probes and technologies. As key components of cellular membranes, lipids also serve as signaling molecules and modify functions of proteins through either covalent or non-covalent interactions. Aberrant regulation of lipid signaling has been correlated with various diseases including cancer, diabetes, and neurodegenerative diseases. Consequently, many lipid-related proteins or processes have been used as therapeutic targets. However, lipids are dynamically metabolized and transported, making it difficult to illustrate their roles in development and diseases with limited availability of probes and technologies for lipid studies. Our research will provide novel probes, assays, and technologies to address these issues. The active projects in the lab include: 1) develop novel technologies to synthesize complex lipids, particularly phosphatidylinositides, and identify their interacting proteins in live cells; 2) develop new small molecule sensors and inhibitors for lipid metabolic enzymes such as PI3K and PLC; and 3) investigate cellular functions of lipids in different processes, particularly those regulated by small GTPases.
Research in the Zhang lab is focused on understanding the roles of endogenous small molecules, particularly phospholipids, in cell signaling events that are responsible for both normal development and diseases. Phospholipids play essential roles in all living organisms. Other than being major membrane constituents in cells, many phospholipids function as signaling molecules. Consequently, abnormal levels of phospholipids and aberrant regulation of their metabolizing enzymes have been associated with onset and progression of various diseases. However, how phospholipid signaling pathways regulate normal development and diseases is still poorly understood, largely due to their dynamic metabolism in the cells and the lack of available reagents and assays for phospholipids and their metabolic enzymes. I am interested in three different approaches to profile and understand phospholipids: 1) develop efficient methods and technologies to synthesize phospholipids and identify their interacting proteins; 2) develop small molecule sensors and inhibitors for different phospholipid metabolic enzymes; and 3) investigate the cellular functions of known and unknown phospholipids, particularly their synergistic actions with small GTPases ADP-ribosylation factors in regulating protein trafficking in signaling transduction. More recently, we have also extended our efforts to drug discovery towards diseases where phospholipid metabolizing enzymes are dysregulated. Toward this end, we are constructing library of small molecules with unique structures and
Phosphatidylinositides (PIs) are a family of anchoring lipids with different combinations of phosphate groups around the inositol ring. Due to their functions of membrane recruitment and activation of downstream effector proteins, PIs are among the most versatile endogenous regulatory small molecules. Dys-regulation of PI signaling has been implicated in diseases such as Low syndrome, cancer, and myotubular myopathy. We are generating an array of natural and unnatural PIs to systematically identify PI-interacting proteins for novel drug target discovery and disease diagnosis. To facilitate these processes, we are developing new technologies of tag-based enzymatic synthesis and target identification as well as small molecule arrays.
To understand the details on how PIs are regulated in living cells, we have developed fluorescence-based reporters for PI-metabolic enzymes PLC and PI3K. These reporters are then used to monitor PLC and PI3K activity in the cells, and further utilized in high throughput screen to identify small molecule inhibitors.
GTPase-activating proteins for the ADP-ribosylation factors (ARFGAPs) play important roles in many biological processes, including vesicle trafficking and cytoskeleton reorganization. We recently identified a small molecule ARFGAP inhibitor from a high throughput chemical screen of the Wnt signaling pathway. We are exploring the functions and mode of actions of this molecule in membrane trafficking, cell migration, and neurite
- Huang, W.; Wang, X.; Endo-Streeter, S.; Barrett, M.; Waybright, J.; Wohlfeld, C.; Hajcek, N.; Harden, T. K.; Sondek, J.; Zhang, Q. A Membrane-associated, Fluorogenic Reporter for Mammalian Phospholipase C Isozymes. Biol. Chem. 2017, in press. DOI: 10.1074/jbc.RA117.000926.
- Waybright, J.; Huang, W.; Proctor, A.; Wang, X.; Allbritton, N. L.; Zhang, Q. Required Hydrophobicity of Fluorescent Reporters for Phosphatidylinositol Family of Lipid Enzymes. Bioanal. Chem. 2017, 409, 6781-6789.
- Tan, L.; Zhou, T.; Cederquist, G.; Mukherjee, S.; Kristen, B.; Zhang, Q.; Schwartz, R.; Evans, T. R.; Chen, S. High Content Screening in hESC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain. Cell Stem Cell 2017, 21, 274-283.
- Singh, M. H.; Waybright, J.; Zhang, Q. A Facile Method to Enable a Model Phospholipid Cell-permeable and Photoactivatable. Tetrahedron 2017, 73, 3677-3683.
- Gao, H.; Sun, W.; Song, Z.; Yu, Y.; Wang, L.; Chen, X.; Zhang, Q. A Method to Generate and Analyze Modified Myristoylated Proteins. Chembiochem 2017, 18, 324-330.
- Seo, J. B.; Jung, S. R.; Huang, W.; Zhang, Q.; Koh, D. S. Charge Shielding of PIP2 by Cations Regulates Enzyme Activity of Phospholipase C. PLoS One 2015, 10, e0144432.
- Singh, M. H.; Gao, H.; Sun, W.; Song, Z.; Schmalzigaug, R.; Premont, R. T.; Zhang, Q. Structure-activity Relationship Studies of QS11, a Small Molecule Wnt Synergistic Agonist. Med. Chem. Lett. 2015, 25, 4838-4842.
- Huang, W.; Zhang, Q. Fluorous Photoaffinity Labeling to Probe Protein-Small Molecule Interactions. Methods Mol. Biol. 2015, 1263, 253-261.
- Charpentier, T. H.; Waldo, G. L.; Barrett, M. O.; Huang, W.; Zhang, Q.; Harden, T. K.; Sondek, J. Membrane-induced Allosteric Control of Phospholipase C-β Isozymes. Biol. Chem. 2014, 289, 29545-29557.
- Huang, W.; Proctor, A.; Sims, C. E.; Allbritton, N. L.; Zhang, Q. Fluorous Enzymatic Synthesis of Phosphatidylinositides. Commun. 2014, 50, 2928-2931.
- Huang, W.; Barrett, M.; Hajicek, N.; Hicks, S.; Harden, T. K.; Sondek, J.; Zhang, Q. Small Molecule PLC Inhibitors from a Novel High Throughput Screen. Biol. Chem. 2013, 288, 5840-5848.
- Wang, X.; Barrett, M.; Sondek, J.; Harden, T. K.; Zhang, Q. Fluorescent Phosphatidylinositol 4,5-Bisphosphate Derivatives with Modified 6-Hydroxy Group as Novel Substrates for Phospholipase C. Biochemistry 2012, 51, 5300-5306.
- Huang, W.; Sun, W.; Song, Z.; Yu, Y.; Chen, X.; Zhang, Q. Incorporation of a Fluorous Diazirine Group into Phosphatidylinositol 4,5-Bisphosphate to Illustrate its Interaction with ADP-ribosylation Factor 1. Biomol. Chem. 2012, 10, 5197-5201.
- Song, Z.; Huang, W.; Zhang, Q. Isotope-coded, Fluorous Photoaffinity Labeling Reagents. Commun. 2012, 48, 3339-3341.
- Huang, W.; Jiang, D.; Wang, X.; Sims, C. E.; Allbritton, N. L.; Zhang, Q. Kinetic Analysis of PI3K Reactions with Fluorescent PIP2 Anal. Bioanal. Chem. 2011, 401, 1881-1888.
- Sun, W.; Vanhooke, J.; Sondek, J.; Zhang, Q. High Throughput Fluorescence Polarization Assay for the Enzymatic Activity of GTPase-activating Protein of ADP-ribosylation Factor (ARFGAP). Biomol. Screen. 2011, 16, 717-723.
- Huang, W.; Hicks, S. N.; Sondek, J.; Zhang, Q. A Fluorogenic, Small Molecule Reporter for Mammalian Phospholipase C Isozymes. ACS Chem. Biol. 2011, 6, 223-228.
- Liu, R.; Xu, R.; Chen, M.; Weiwer, M.; Zhou, X.; Bridges, A. S.; DeAngelis, P. L.; Zhang, Q.; Linhardt, R. J.; Liu, J. Chemozymatic Design of Heparan Sulfate Oligosaccharides. Biol. Chem. 2010, 285, 34240−34249.
- Jones, C. A.; Nishiya, N.; London, N. R.; Zhu, W.; Sorensen, L. K.; Chan, A.; Lim, C. J.; Chen, H.; Zhang, Q.; Schultz, P. G.; Hayallah, A. M.; Thomas, K. R.; Famulok, M.; Zhang, K.; Ginsberg, M. H.; Li, D. Y. Slit2-Robo4 Signaling Promotes Vascular Stability by Blocking Arf6 Activity. Nature Cell Biol. 2009, 11, 1325-1331.
- Song, Z. and Zhang, Q. Fluorous Aryl Diazirine Photoaffinity Labeling Reagents. Lett. 2009, 11, 4883-4885.
A postdoc position in Cell Biology is available immediately in the lab. The broad objective of the project is to understand the cellular functions and mechanisms of small molecules that monitor and regulate lipid signaling, particularly those related to phosphatidylinositides and small GTPases. To be considered, applicants must have a Ph.D. in Cell Biology or a related field. Experience with cell signaling studies is required and expertise in microscopy is preferred. Compensation is commensurate with experience. Please send a detailed cover letter, curriculum vitae, and names of two references to Dr. Qisheng Zhang (email@example.com).
We also look for graduate students and undergraduate students who are highly motivated, open-minded, and enthusiastic about working on multi-disciplinary research projects to join the lab.
Holiday Lunch 2011
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ACCEPTING DOCTORAL STUDENTS
The Zhang lab studies lipid signaling pathways that are involved in human disease by developing novel chemical probes and technologies. They currently focus on discovering new bioactive lipids, developing small molecule modulators and biosensors for lipid metabolizing enzymes, and applying their research results to novel diagnosis and treatment of cancer, Parkinson’s disease, and antimicrobial resistance.