Dr. Fu’s Lab
Awards and Honors
Profiled on the Journal of Biological Chemistry for the article “Lipid-Tuned Zinc Transport Activity of Human ZnT8 Correlates with Risk for Type-2 Diabetes.” (2016)
In past three years, I have been focusing on the biochemistry and cell functional studies of zinc transporters, which include zinc influx transporters ZIPs and zinc efflux transporters ZnTs. As Diabetes becomes one of the most popular diseases world-wide, seeking novel technology with high sensitivity and accuracy for detection, diagnosis and therapeutic treatment is imperatively under way. The discovery of Diabetes associating with human pancreatic zinc transporter ZnT8 is a big breakthrough. Human ZnT8 is highly expressed in pancreatic β-cells, responsible for zinc enrichment in insulin secretory granules and plays regulatory roles for insulin maturation, crystallization and secretion, as for controlling glucose level in blood and urine. However, the detail biochemical characterization and physiological molecular function of ZnT8 are poorly understood. For the first time, we have successfully expressed and purified the functional human ZnT8, reconstituted into proteoliposomes, largely explored the dynamic zinc transport activities of R325W polymorphic variants in vitro, and suggested human ZnT8 inhibition may be a therapeutic strategy to reduce Diabetes risk. Also, we studied ZnT8 surface display in response to glucose stimulated insulin secretion (GSIS), demonstrated insulin secretion is coupled with ZnT8 self-antigen surface exposure, and proposed ZnT8 as a surface marker to potentially identify pancreatic phenotypes in vivo. Our recent data showed using only one variant of the functional ZnT8 in proteoliposomes can detect Diabetes with 76% sensitivity and 97% specificity among over 300 human sera on gold plasmonic chips. The highly achieved detection ability for Diabetes by autoantibodies in sera against ZnT8 in proteoliposomes is striking, because the lipids can maintain ZnT8 proper folding and intact structure even dried. We used human ZnT8 in proteoliposomes to immunize mice and generated confirmation specific monoclonal antibodies to investigate ZnT8 function in vitro and in vivo. We integrate biochemistry, structural biology, cell biology, genetics and animal studies to understand the ZnT8 function and the relationship with Diabetes, and to look for novel ZnT8 antibodies and small molecular ZnT8 inhibitors that could be used for Diabetes earlier stage diagnosis and therapeutic treatment, which will benefit millions of lives.