Zhe Lu, MD, PhD

Description of Research Expertise

Research Interests
Mechanism of ion channels and pathogenesis of channelopathy

Key words: Ion channels, inhibitors, ion permeation and selectivity, channel gating, channelopathy.

Description of Research
Our laboratory investigates both the fundamental mechanisms of ion channels and the pathogenesis of ion channel-based genetic diseases such as cystic fibrosis and diabetes, and develops novel pharmacological agents to control the activity of specific types of ion channels. Ion channels are a class of highly specialized membrane proteins that allow ions to flow across the cell membrane in a selective manner. The opening and closing of ion channels are precisely regulated by the intricate cell signaling system. Ionic currents through ion channels generate electrical voltage across the cell membrane which underlies the electrical impulses in nerve, muscle and endocrine cells.
Currently, we are studying three types of ion channels, i.e., potassium channels, the cGMP-gated cation channel, and the cystic fibrosis conductance regulator chloride channel. Using a combined structural and functional approach, we investigate the mechanisms underlying the ability of potassium channels to perform various important biological tasks, such as generating action potentials, modulating the communications between neurons, controlling the rate of the cardiac pacemaker, and coupling the blood glucose level to insulin secretion. We also examine the mechanisms that enable the cGMP-gated channel to mediate visual photo-transduction in the eye. Recently, we have ventured into the area of how phospholipases regulate ion channel function, a venture that has provided us with new insight into the pathogenesis of cystic fibrosis. Another area of our research is to develop novel protein inhibitors for various types of biologically important ion channels through both passive screening and active protein design-and-engineering. Using the thermodynamic mutant cycle analysis, we examine the molecular mechanisms of channel inhibition, mechanisms that give rise to the molecular specificity between a given inhibitor and its targeting channel.
Rotation Projects
Rotating students will participate in the studies of structure-function of ion channels and pathogenesis of channelopathy. The projects will involve molecular biological, protein-biochemical and electrophysiological techniques such as gene construction, site-directed mutagenesis, expression of recombinant proteins in bacterium, high performance liquid chromatography (HPLC), two-electrode voltage-clamp, patch-clamp and crystallography.

Lab personnel:
Dr. Kyuwon Baek, HHMI Post-doctoral Associate
Mr. David Combs, M.D.-Ph.D. Student
Dr. David Lin, HHMI Post-doctoral Associate
Dr. Yajamana Ramu, Research Investigator
Dr. Marriane Shin, Research Specialist
Dr. Yanping Xu, Research Investigator