Honors & Awards


  • Centennial Teaching Award, Stanford University - Office of the Vice Provost for Teaching and Learning (2016)

Education & Certifications


  • B.S., Ouachita Baptist University, Arkadelphia, Arkansas, Majors in Professional Chemistry and Physics, Minors in Mathematics and Biology (2014)

Stanford Advisors


Lab Affiliations


All Publications


  • CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition. Endocrinology Abdolazimi, Y., Lee, S., Xu, H., Allegretti, P., Horton, T. M., Yeh, B., Moeller, H. P., Nichols, R. J., McCutcheon, D., Shalizi, A., Smith, M., Armstrong, N. A., Annes, J. P. 2018

    Abstract

    Pharmacologic expansion of endogenous β-cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2,400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase (JNK) inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual specificity tyrosine-phosphorylation-regulated kinases (DYRK1A/B) inhibition. In contrast to rat β-cells, which were broadly growth responsive to compound treatment, human β-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3β (GSK-3β) or transforming growth factor-β (ALK5/TGF-β) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T-cells (NFAT) as the primary mechanism of human β-cell replication induction. However, inhibition of NFAT activity had limited impact on CC-401-induced β-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the β-cell replication-inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control β-cell replication and leverage a novel DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control β-cell growth.

    View details for DOI 10.1210/en.2018-00083

    View details for PubMedID 29514186

  • The IFN-lambda-IFN-lambda R1-IL-10R beta Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity IMMUNITY Mendoza, J. L., Schneider, W. M., Hoffmann, H., Vercauteren, K., Jude, K. M., Xiong, A., Moraga, I., Horton, T. M., Glenn, J. S., de Jong, Y. P., Rice, C. M., Garcia, K. C. 2017; 46 (3): 379-392
  • Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding BIOCHEMICAL JOURNAL Visperas, P. R., Winger, J. A., Horton, T. M., Shah, N. H., Aum, D. J., Tao, A., Barros, T., Yan, Q., Wilson, C. G., Arkin, M. R., Weiss, A., Kuriyan, J. 2015; 465: 149-161

    Abstract

    Zeta-chain associated protein of 70 kDa (ZAP-70) and spleen tyrosine kinase (Syk) are non-receptor tyrosine kinases that are essential for T-cell and B-cell antigen receptor signalling respectively. They are recruited, via their tandem-SH2 (Src-homology domain 2) domains, to doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) on invariant chains of immune antigen receptors. Because of their critical roles in immune signalling, ZAP-70 and Syk are targets for the development of drugs for autoimmune diseases. We show that three thiol-reactive small molecules can prevent the tandem-SH2 domains of ZAP-70 and Syk from binding to phosphorylated ITAMs. We identify a specific cysteine residue in the phosphotyrosine-binding pocket of each protein (Cys39 in ZAP-70, Cys206 in Syk) that is necessary for inhibition by two of these compounds. We also find that ITAM binding to ZAP-70 and Syk is sensitive to the presence of H2O2 and these two cysteine residues are also necessary for inhibition by H2O2. Our findings suggest a mechanism by which the reactive oxygen species generated during responses to antigen could attenuate signalling through these kinases and may also inform the development of ZAP-70 and Syk inhibitors that bind covalently to their SH2 domains.

    View details for DOI 10.1042/BJ20140793

    View details for Web of Science ID 000351685300012

    View details for PubMedID 25287889