University of Colorado
Skaggs School of Pharmacy and Pharmaceutical Sciences
Department of Pharmaceutical Sciences
Mail Stop C238, Room V20-2121
12850 E. Montview Blvd
Aurora, CO 80045
Pharmacy and Pharmaceutical Sciences Building (V20)
Pharmacy and Pharmaceutical Sciences Building (V20)
Room 2450 A,B,C
- Member, Graduate Program in Immunology
- Member, Graduate Program in Toxicology
- Member, Graduate Program in Pharmaceutical Sciences
- Member, Graduate Program in Structural Biology and Biochemistry
- Member, Colorado Clinical and Translational Sciences Institute
- Affiliate Member, University of Colorado Cancer Center
- Faculty, Department of Immunology and Microbiology, School of Medicine
- Faculty, Department of Biomedical Research, National Jewish Health
Training and Education
- B.E., Beijing University of Chemical Technology, China (Biochemical Engineering)
- PhD, Uppsala Biomedical Centre, Sweden (Molecular Biology)
- Post-doctoral Fellow, Purdue University (Structural Biology)
- Instructor, Howard Hughes Medical Institute, National Jewish Health (Immunology)
The molecular mechanisms of allergy and autoimmunity:
Our research is focused on understanding the mechanisms of metal induced allergy and autoimmune diseases and will provide the molecular basis upon which we may be able to design therapeutic compounds to prevent or treat these diseases. Environmental exposure to heavy metals plays an important role in the development of allergies and autoimmune diseases. Metals, for example nickel, and other small molecules can be unconventional components of TCR ligands and, in this form, can cause some of the most common allergic diseases. We are studying how self-peptides bound to metals create neoantigens and activate pathogenic T cells. This type of post-translational modification (PTM) may contribute to the pathogenesis of rheumatoid arthritis (RA) and Type 1 diabetes (T1D). My lab is trying to elucidate the different mechanisms of cadmium, nickel and beryllium T cell activation, and identify metal reactive self-peptides. We will employ structural biology, mass spectrometry, single cell sequencing and T cell transcriptome/epigenome analysis to unravel the mechanisms of metal immunotoxcity. Another focus of my lab is researching how other forms of PTMs (peptide fusion, disulfide modification and chemical modifications) can create T cell neoantigens in autoimmune diseases.
Redox signaling in the immune system:
Oxidative stress involves the oxidation and reduction of cysteine residues in critical thiol containing proteins. Changes in the structure and activity of these proteins can initiate cell responses, or modify the response of cells to other signals. We are interested in the thioerdoxin depedentregulatory mechanisms in immune system, for example, apoptosis signal-regulating kinase 1 (ASK1). Reactive oxygen species regulate the ASK1-JNK/p38 pathway through glutaredoxin and thioredoxin. The pathogens, like bacteria and parasites, have a unique redox signaling pathways from human. By targeting these pathways, we could identify potential novel drug candidates. We are focusing on studying the thioredoxin related enzymes and redox-based gene regulation of pathogens.
Immunotherapy targeting neoantigens of allergy, autoimmune disorders and cancer:
Our long-term goal is to find safe therapeutic neoantigen specific approaches to prevent or delay the development of allergy, autoimmunity and cancer. One of our focuses is the use of neoantigen specific monoclonal antibodies (mAbs) to block antigens, thus restoring immune tolerance. This approach is likely to provide greater safety and be more effective than general immune suppression which can have unwanted consequences. These mAbs can be used in chimeric antigen receptor (CAR)-redirected T cell therapy targeting disease relevant neoantigens on antigen presenting cells (APCs) as a novel therapy. In a second approach, T cell receptors (TCRs) can be engineered to be more potent, long-lasting and specific to neoantigens. We are designing small molecules that can bind to the unique neoantigens and thus block the interaction between APCs and T cells, and developing these compounds to treat immune diseases. Promising drug candidates can be optimized to further avoid eliciting immune responses.
- IMMU 7604 Special Topics in Signal Transduction in the Immune System
- IMMU 7662 Immunology core course
- PHRD 7812 Seminar in Pharmaceutical Sciences
- PHRD 6915 Seminar Research 1
- TCR interaction with peptides that mimic Ni++ offers insight into allergic Ni++ recognition Yin, L, Crawford, F, Marrack P, Kappler JW, and Dai S. 2012. Proc Natl Acad Sci USA 109(45):18517-22
- Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. 2014. Clayton GM, Wang Y, Crawford F, Novikov A, Wimberly BT, Kieft JS, Falta MT, Bowerman NA, Marrack P, Fontenot AP, Dai S*, Kappler JW*, Cell. 158(1):132-42. *Corresponding author
- Insights on the enzymatic and structural basis of Echinococcus granulosus thioredoxin glutathione reductase inhibition by gold(I). 2017. Salinas G, Gao W, Wang Y, Bonilla M, Yu L, Novikov A, Virginio VG, Ferreira HB, Vieites M, Gladyshev VN, Gambino D and Dai S, Antioxidants and Redox Signaling. 27(18):1491-1504. (Cover story)
- Using DR52c/Ni2+ Mimotope tetramers to detect Ni2+ reactive CD4+ T cells in patients with joint replacement failure. 2017. Zhang Y, Wang Y, Anderson K, Novikov A, Liu Z, Pacheco K and Dai S, Toxicology and Applied Pharmacology. 331:69-75.
- C-terminal modification of the insulin B: 11-23 peptide creates super-agonists in type-1 diabetes in mouse and human type 1 diabetes. 2018. Wang Y, Sosinowski T, Novikov A, Crawford F, Neau D, Yang J, Marrack P, Kappler J, and Dai S. Proc Natl Acad Sci USA 115(1):162-167
- DksA-DnaJ redox interactions provide a signal for the activation of bacterial RNA polymerase. 2018. Kim JS, Liu L, Fitzsimmons LF, Wang Y, Crawford MA, Mastrogiovanni M, Trujillo M, Till JKA, Radi R, Dai S, Vázquez-Torres A. Proc Natl Acad Sci U S A. 115(50):E11780-E11789.