The long-term goal of our research group is to develop molecular tools for monitoring and manipulating various biological processes with a spatiotemporal control to advance neuroscience research and potential therapeutics.

We utilize cutting-edge protein engineering methods, including directed evolution, to engineer these new tools. Various model systems—including mammalian cell culture, neuronal culture and animal models—are used to test the performance of our tools. The following are examples of research areas that we are interested in:

Designing tools for investigating GPCR signaling at the neuronal circuit level

G-protein coupled receptor (GPCR) signaling regulates many physiological processes and behaviors and underlies various neurological and neurodegenerative diseases. For example, opioid signaling regulates pain perception, euphoria and breathing, and also plays a role in alcohol and drug abuse. Dopamine signaling regulates reward, learning and motor functions, and also plays an important role in schizophrenia and Parkinson’s disease. There has been tremendous development in pharmacological approaches to studying GPCR signaling; however, our understanding of how GPCRs act at the brain/neuronal circuit level is still limited due to the lack of genetically-encoded tools to monitor or modulate GPCR activity with high spatiotemporal control.

Endogenous GPCR signaling is spatiotemporally-regulated by the precise release of their ligands and uptake by receptors. Endogenous ligands can act either locally via synaptic transmission or have long-range effects via volume transmission. Upon activation, GPCRs can cause either excitatory or inhibitory effects on neuronal activity depending on their downstream molecular events, and the cell types and neuronal circuits they are expressed in. Therefore, to better understand a GPCR’s role in behaviors and various physiological processes, it is important to investigate, at the neuronal circuit level: 1) when and where the endogenous ligands are released, and 2) the effects of modulating a GPCR’s activity in defined neuronal populations. We aim to design genetically-encoded tools for addressing these challenges.

Designing new classes of optogenetic and chemogenetic tools for prolonged neuronal silencing with a fast temporal control

Optogenetic and chemogenetic tools have revolutionized neuroscience research, and they also hold tremendous promise for gene therapy of neurological disorders, including epilepsy Schizophrenia and anxiety disorders. Among the approximately 65 million people worldwide affected by epilepsy, 30% are resistant to current medicine but could significantly benefit from new gene therapies that can quickly and effectively suppress the increased neuronal activities during seizures; however, we still lack tools that enable effective and prolonged neuronal silencing in quick response to abnormal neuronal activities. We aim to engineer modular biological designs for temporally-controlled alteration of specific neuronal pathways for neuroscience research and potential therapeutics.

Designing functional nanobodies as research tools

Nanobodies, derived from the single-chain antibodies from Camelidae, provide excellent alternatives to conventional antibodies for recognizing various protein targets. They are much smaller, more stable and soluble than conventional antibodies. Due to their advantages, nanobodies have been widely applied as research tools and hold tremendous promise as therapeutic reagents. We are designing synthetic nanobodies for various biological targets, including a nanobody that can selectively recognize a-synuclein preformed fibrils (PFFs) for the study of the functional roles of a-synuclein PFF in the progression of Parkinson’s disease.