Academic Appointments

All Publications

  • SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas. Cell reports Armstrong, N., Storey, C. M., Noll, S. E., Margulis, K., Soe, M. H., Xu, H., Yeh, B., Fishbein, L., Kebebew, E., Howitt, B. E., Zare, R. N., Sage, J., Annes, J. P. 2022; 38 (9): 110453

    Abstract

    Inherited pathogenic succinate dehydrogenase (SDHx) gene mutations cause the hereditary pheochromocytoma and paraganglioma tumor syndrome. Syndromic tumors exhibit elevated succinate, an oncometabolite that is proposed to drive tumorigenesis via DNA and histone hypermethylation, mitochondrial expansion, and pseudohypoxia-related gene expression. To interrogate this prevailing model, we disrupt mouse adrenal medulla SDHB expression, which recapitulates several key molecular features of human SDHx tumors, including succinate accumulation but not 5hmC loss, HIF accumulation, or tumorigenesis. By contrast, concomitant SDHB and the neurofibromin 1 tumor suppressor disruption yields SDHx-like pheochromocytomas. Unexpectedly, invivo depletion of the 2-oxoglutarate (2-OG) dioxygenase cofactor ascorbate reduces SDHB-deficient cell survival, indicating that SDHx loss may be better tolerated by tissues with high antioxidant capacity. Contrary to the prevailing oncometabolite model, succinate accumulation and 2-OG-dependent dioxygenase inhibition are insufficient for mouse pheochromocytoma tumorigenesis, which requires additional growth-regulatory pathway activation.

    View details for DOI 10.1016/j.celrep.2022.110453

    View details for PubMedID 35235785

  • A Wireless Implantable Potentiostat for Programmable Electrochemical Drug Delivery IEEE Biomedical Circuits and Systems (BIOCAS) Wang, M. L., Yeon, P., Chamberlayne, C. F., Mofidfar, M., Xu, H., Annes, J. P., Zare, R. N., Arbabian, A. 2021

    View details for DOI 10.1109/BioCAS49922.2021.9644991

  • On-demand drug release from polypyrrole nanoparticulate films Chamberlayne, C., Baltsavias, S., Xu, H., Arbabian, A., Annes, J., Zare, R. AMER CHEMICAL SOC. 2019

    View details for Web of Science ID 000525055501160

  • CC-401 Promotes beta-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition ENDOCRINOLOGY Abdolazimi, Y., Zhao, Z., 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; 159 (9): 3143–57

    View details for DOI 10.1210/en.2018-00083

    View details for Web of Science ID 000446426000002

  • CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition. Endocrinology Abdolazimi, Y. n., Lee, S. n., Xu, H. n., Allegretti, P. n., Horton, T. M., Yeh, B. n., Moeller, H. P., Nichols, R. J., McCutcheon, D. n., Shalizi, A. n., Smith, M. n., 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 PubMedID 29514186

  • Genetic Disruption of Adenosine Kinase in Mouse Pancreatic ß-Cells Protects Against High Fat Diet-Induced Glucose Intolerance. Diabetes Navarro, G., Abdolazami, Y., Zhao, Z., Xu, H., Lee, S., Armstrong, N. A., Annes, J. P. 2017

    Abstract

    Islet β-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of β-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate β-cell replication. Here, we evaluated whether ADK disruption in mouse β-cells affects β-cell mass and/or protects against high-fat diet (HFD)-induced glucose dysregulation. Mice targeted at the Adk locus were bred to Rip-Cre and Ins1-Cre/ERT(1Lphi) mice to enable constitutive (βADKO) and conditional (iβADKO) disruption of ADK expression in β-cells, respectively. Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion (GSIS) were longitudinally monitored in normal chow (NC)-fed and HFD-fed mice. In addition, β-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult βADKO and iβADKO mice displayed glucose tolerance, insulin tolerance and β-cell mass comparable to control animals. By contrast, HFD-fed βADKO and iβADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased β-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive β-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive β-cell response.

    View details for DOI 10.2337/db16-0816

    View details for PubMedID 28468960