Our lab is interested in identifying functional small molecules from synthetic and endogenous chemical libraries and studying how these molecules regulate disease-related cell signaling. Other than traditional methods in chemical synthesis, molecular and cell biology and the emerging technique of high throughput screening, we also develop new techniques of tag-based biosynthesis and enzyme profiling, as well as small molecule array, to facilitate research. Currently, we are working on the following three projects:

1) Chemical approaches to probe Phosphatidylinositide-regulated cellular processes.

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.

2) Reporters and Inhibitors of PI-metabolic enzymes.

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.

3) Small molecule ARFGAP inhibitors to dissect cell signaling.

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 outgrowth.