Structure and function of transporters in neurons
The aim of my research is to elucidate the molecular function, architecture, and high-affinity drug binding sites of synaptic vesicle transporters in neurons by studying their function using biochemical techniques and determining their structures using single particle cryo-EM. I am particularly interested in understanding the conformational changes and mechanism associated with transporters. I have developed methods for large-scale expression, stabilization by drugs, and for the production of antibodies which recognize transporters. The use of transporter-antibody complexes is essential in order to provide mass and molecular features to assist in cryo-EM reconstructions because these transporters are small membrane proteins which are largely ensconced within membrane. Atomic structures of transporters in complex with therapeutic drugs are essential for the design of better small-molecule therapeutics with higher specificity and fewer side-effects and will also advance efforts toward understanding the function of these transporters.
Aarhus University, Department of Physiology
Visiting student in lab of Dr. Jens Peter Anderson, 2010
University of British Columbia, Department of Biochemistry and Molecular Biology
Ph.D. in lab of Dr. Rober Molday, 2007-2013
Oregon Health & Science University, Vollum Institute
Postdoctoral training in lab of Dr. Eric Gouaux, 2013-2020
3501 Fifth Avenue
Pittsburgh, PA 15213
Phone: (412) 648-8077
Fax: (412) 648-9008
Website link: coming soon
Our lab is interested in developing new tools for mapping 3D organization of biomolecules and probing biological processes in the tissue and organism.
Complex biological systems are delicate machines consist of building blocks (such as proteins, nucleic acids, lipids, and carbohydrates) that are precisely organized in the nanoscale. This presents a fundamental challenge for humanity to understand the biology and/or pathology underlying these complex systems. To gain the insight into physiological/pathological functions, one might need to map a large diversity of nanoscale building blocks, over a wide spatial scale. To tackle this challenge, we are developing a set of novel technologies that enable large scale visualization of biological samples with nanoscale precision, by physically expanding the sample rather than magnifying the light from the sample via lenses. This principle is called expansion microscopy (ExM). By combining various material engineering and chemical approaches, we are advancing ExM-based tools that may elucidate biological insights into the brain and other complex systems, such as cancer and infectious diseases.
B.S. Chemistry, 2009, Sun Yat-sen University
PhD Chemistry, 2014, University of Alberta
2017, Bioengineering/Pathology, Massachusetts Institute of Technology
Zhao Biophotonics Laboratory
Carnegie Mellon University
202A Mellon Institute
Department of Biological Sciences
4400 Fifth Ave
Pittsburgh, PA 15213
Structural biology, pharmacology and signaling of G protein-coupled receptors (GPCRs) and drug development
My group studies structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) as important cell membrane-embedded receptors. GPCR family has over 700 members. They transduce signals from extracellular signaling molecules to intracellular effectors through conformational changes within the receptors to mediate and regulate a broad spectrum of physiological and pathological processes. GPCRs have been heavily investigated in the pharmaceutical industry, and they constitute 30-40% of current drug targets. My lab utilizes structural biology approaches including X-ray crystallography and cryo-electron microscopy (cryo-EM) and functional studies including ligand-binding assays and cellular signaling assays to explore the molecular mechanisms underlying the signal transduction of GPCRs. Currently, we focus on two groups of GPCRs, the chemotactic GPCRs involved in inflammatory diseases and the neurotransmitter GPCRs involved in neurological and psychiatric disorders. In addition, we also develop new GPCR antibodies as novel therapeutic candidates through combinatorial biology approaches such as yeast display.
BS 2003, University of Science and Technology of China
PhD 2008, University of Science and Technology of China
2008-2014, Dr. Brian Kobilka's group, School of Medicine, Stanford University
Department of Pharmacology and Chemical Biology
School of Medicine, University of Pittsburgh
203 Lothrop St
Our laboratory is interested in the fundamental question of how the cell controls the morphology and structure of its membranes. To this end, we are particularly interested in understanding endosomal sorting and the molecular mechanisms of endosomal membrane remodeling. Remodeling is performed by members of several protein families, including the SNX-BAR proteins and the dynamin-related proteins (DRPs). SNX-BAR and DRP mutations are both associated with health challenges, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
We use structural and biophysical approaches, supplemented with in vivo and high throughput genetic studies in the model organism S. cerevisiae. Recently, we used cryo-electron microscopy and X-ray crystallography, combined with live cell imaging and functional cell biological approaches, to characterize a retromer-dependent SNX-BAR involved in retrograde trafficking from the endosome as well as a DRP involved in endosomal membrane remodeling. In both cases, the structures we generated provided novel insights into the regulation of their function by self-assembly.
Our current work aims to understand how various SNX-BAR complexes are regulated and how they engage with their respective cargoes and binding partners, including members of the DRP family.
Department of Cell Biology
University of Pittsburgh
3500 Terrace Street
Pittsburgh, PA 15261
The Carlson lab studies ion channels and fertilization.
Our lab studies excitable using biophysical tools such as electrophysiology, photometry and fluorometry, as well as diverse biochemical methods. We currently have two research directions, uncovering the earliest events of fertilization, and studying how ion channels are regulated.
Fertilization: Fertilization of an egg by more than one sperm, a condition known as polyspermy, presents one of the earliest barriers to successful reproduction. Polyspermy leads to gross chromosomal abnormalities and is lethal to the developing embryos. Due to these catastrophic consequences, eggs employ multiple processes that protect the protect the nascent embryo. The two most widely studied are called the fast and slow blocks to polyspermy. As their names imply, these blocks occur at different times to fertilization. In the slow block to polyspermy, eggs release material into the extracellular space, and within minutes of its release, this material transforms the egg from a gamete ready for sperm entry, to a structure unable to permit fertilization. We seek to identify the molecular mechanisms that enable the released material to facilitate this transformation. The slow block is used by eggs from nearly all sexually reproducing animals. By contrast, the fast block to polyspermy is mainly used by eggs from external fertilizers. In the fast block, fertilization activates a depolarization of the egg. By currently unknown mechanisms, sperm can bind to, but will not enter, a depolarized egg. Although fertilization-signaled depolarizations have been recorded for many years, we are only beginning to uncover the signaling pathways that activate the fast block. We have identified the first molecular identity of a channel that mediates the fast block, and now seek to uncover the pathway that links sperm entry to channel activation.
Ion channel regulation: The Ca2+-activated Cl- channel, TMEM16A plays an important role in human health. TMEM16A channels play important physiologic roles in diverse tissues including excitability of the insulin-producing pancreatic β cells and excretion by the salivary gland. Overexpression of TMEM16A also plays an important role in the development of several diseases. For example, 80% of craniofacial squamous cell carcinomas are marked by TMEM16A overexpression, and TMEM16a inhibition slows the progression of this cancer. TMEM16A channel expression is increased in airway smooth muscle and secretory cells of asthmatic patients, and blocking its currents attenuates the major symptoms of the disease by restoring cholinergic responsiveness and reducing mucus secretion. Recently, TMEM16A has been proposed to be a novel target for cystic fibrosis treatments. Despite this robust body of evidence documenting a critical role for TMEM16A in human health and disease, little is known about how this channel is regulated in vivo; it is imperative to understand how this channel is regulated in order to exploit this regulation therapeutically. We are employing electrophysiology to uncover how TMEM16A channels are regulated by diverse cellular signals.
PhD 2006, University of Washington
Department of Physiology and Biophysics, University of Washington
University of Pittsburgh
Department of Biological Sciences
201 Life Sciences Annex
4249 Fifth Avenue
Pittsburgh, PA 15260