Research Areas
1. Calcium Channels, TCR signaling, & Inter-Organelle Communication
Calcium and TCR signaling
1A. Calcium signaling, phospholipid metabolism, and lymphocyte activation. Our goal is to illuminate novel regulatory mechanisms of signal transduction that remain unresolved in calcium and phospholipid signaling. We are particularly interested in the calcium release-activated calcium (CRAC) channel made of STIM-ORAI. We identified STIMATE and STIM1b as novel players contributing to calcium signaling heterogeneity, and developed Opto-CRAC and LOCa for optical control of calcium signaling. We are applying these tools to uncover new mechanisms that govern calcium signaling and T cell activation or exhaustion. (NSMB ’10 & ’13; eLife '15; Nat Cell Biol ’15; Nat Commun (x4) ’15, ’19, '20, & ‘21; Adv Sci, '22).
Membrane contact sites
1B. Membrane contact sites formed between two organelles remain as an under-explored territory in cell biology. The Zhou lab has been crafting new molecular tools to accelerate the mechanistic dissection of these elusive subcellular compartments. Tools from the zhou lab in this direction include OptoPB, and LiMETER that enable light-inducible assembly of membrane contact sites and protein-phospholipid interactions with high spatial and temporal precision. We are developing innovative tools to enable precise control of organellar functions, and are also unraveling the functions of several uncharacterized TMEM family proteins. (Nat Commun '15; Nat Cell Biol '15; 'Chem Sci '17; PLOS Biol ' 18; Curr Opin Physiol '22).
2. Optogenetic Engineering
Opsin-free optogenetics
2A. Optophysiology combines biophotonics, genetics, and physiology to enable physiologists to precisely control protein activity, cellular function, and cell-to-cell communications with a simple flash of light. This approach shows great promise in facilitating the mechanistic dissection of physiological processes and the development of precision medicine. The development of next-generation optogenetic tools and devices promises to accelerate both basic and translational researches. (Nat Rev Bioeng '23; Physiol Rev '22; Trends in Genetics '22). A book entitled "Opsin-free Optogenetics: Technology and Applications" is available here.
Optogenetic immunotherapy
2B. Optogenetic immunomodulation. We are among the first to advocate this concept and push forward this nascent field that combines nanotechnology, biophotonics, immuo-engineering with immunotherapy to enable personalized delivery of cancer therapy. Upconversion nanoparticles coupled with opsin-free optogenetics enable wirelss control of immune cells in vivo with high spatial and temporal precision (eLife, '15; ACS Nano '17; Trends in Biotech ’17; Nat Nanotech ’21; Nat Chem Biol '21; Adv Sci ' 21; Clin & Transl Med '22; Nat Rev Bioeng '23). see selected publications
3. Chemical and SynBio Tool Development
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Creating new molecular tools
3A. Expanding the genetically-encoded molecular toolkit.
We are crafting generally-applicable molecular tools for precise control of cell physiology, genome engineering, epigenetic remodeling, and gene transcription. Recent tools made by the Zhou lab include CiDER for DNA modifications, CaRROT for optical control of CRISPR-Cas9 activity, Sunbody/ Moonbody for optical control of nanobody and moonbody, and caffebody for chemogenetic control of biological activities with caffeine. (Physiol Rev ’22; Sci Adv '23; JACS '17 & '20; Curr Opin in Physiology, '21).
Expanding chemogenetic tools
3B. Novel chemically-inducible dimerization (CID) systems. We are also exploring novel chemogenetic approaches with designer GPCRs and chemically-induced proximity (CIP), as well as modular engineering approaches to control antibody-like protein scaffolds or protein binders for conditional control over endogenous proteins. Recent tools developed by the lab include cpRAPID, ChemoID, Chessbody, COSMO, and SAMBA as novel chemical dimerizers. (J Mol Biol '20; Adv Sci '21). see selected publications
4. Synthetic Immunology and Precision Immunotherapy
Programmable control over biologics and 'living' drugs.
Our ultimate goal is to integrate molecular tools from the bench into biologics, antibody-based drugs, and therapeutic immune cells to enable precision immunotherapy, in which the dose, location and duration of both innate and adaptive immune responses can be tailored according to each patient's need. We have multiple patents licensed to achieve this goal.
We are also interested in designing synthetic genetic circuits for therapeutic applications. We are building genetic circuits in therapeutic modalities to generate smart biologics and chimeric antigen receptor T or NK cells (CAR-T and CAR-NK based cellular immunotherapy) for the treatment of human diseases, including cancer, autoimmune disorders and neurodegenerative diseases (Nat Rev Bioeng '23; Trends in Genetics '22; Curr Opin in Biotech '21; Clinical & Translational Medicine '22; CDTM '22) .
A number of technologies from the Zhou lab have been licensed to biotech and pharmaceutic companies to pursue their ultimate medical applications (Nat Rev Bioeng '23; Nat Commun '23; Nat Nanotech '21; Adv Sci '21; ACS Synth Biol '18; Adv Biol '21).
5. Transcriptional and epigenetic regulation in health and disease
We are dedicated to unraveling the intricate connections between epigenetic pathways, transcription factors (NFAT/TFEB/TFE3), and their implications in tumorigenesis. Specifically, our investigations delve into the roles of transcription factors such as NFAT (Cell Chem Biol '19), TFE3 and epigenetic modulators, including non-coding RNAs (Nat Cell Biol '17, DNA methyltransferases (DNMT; Nature Genetics '22), and Ten-eleven Translocation (TET) enzymes (Nature Aging '23).
Meanwhile, we aim to develop novel therapeutics targeting these pivotal molecules to treat cancer (breast cancer, glioblastoma, renal cell carcinoa, leukemia and lymphoma) and immunoinflammatory disorders (Seminars in Cancer Biology '22).
These collaborative and translational efforts are bolstered by the in-house bioinformatics, highthroughput screening and high-content imaging capabilities.