Professor, Cancer Biology - GIDP
Dr. Zhang is a Professor of Pharmacology and Toxicology. She is an internationally recognized leader in the field of the Nrf2-Keap1-ARE signaling pathway. She has been working on the Nrf2 signaling pathway since 2002 and has published over 90 well-received papers as evidenced by the total number of citations (6688) and h-index (37) [Google Scholar as of Aug 24, 2015].
Dr. Zhang has made seminal contributions to both the mechanistic understanding of Nrf2 regulation, as well as the dual role of Nrf2 in human diseases. Her research pioneered the identification of Keap1 as an E3 ubiquitin ligase that constantly targets Nrf2 for ubiquitination and degradation, and the critical role of cysteine residues of Keap1, especially C151, in sensing and regulating the activity of the Nrf2 pathway in response to chemopreventive compounds (canonical mechanism of Nrf2 activation). To help define and utilize the protective function of Nrf2, her team has discovered many chemopreventive small molecules that activate Nrf2 and demonstrated that controlled Nrf2 activation by these chemopreventive compounds protects against many environmental toxicants. For example, Dr. Zhang's team demonstrated the beneficial role of controlled Nrf2 activation by suforaphane, tanshinone I, and bixin in ameliorating lung damage induced by arsenic-containing particles and by ventilation in mice. In 2010, Dr. Zhang's group identified that Nrf2 activation is also regulated by p62, a key adaptor protein in autophagy, in what they termed the noncanonical mechanism of Nrf2 activation (p62-dependent, Keap1-C151-independent). This work linked the oxidative stress pathway with the autophagic proteotoxic stress pathway through p62. Some compounds, such as the carcinogen arsenic, block autophagy, resulting in persistent Nrf2 activation, tipping the role of Nrf2 to the “dark side” by causing tissue damage. However, upregulation of autophagy induces Nrf2 by lysosomal degradation of p62 bound to Keap1, indicating some autophagy activators can also be Nrf2 activators. Encouraged by the benefit of synergistic activation of both Nrf2- and autophagy-mediated stress responses, her group has identified 5 lead compounds that can induced both Nrf2 and autophagy pathways. Therefore it is believable that these dual activators will confer unexpected potential in counteracting toxic gas-induced lung injury through neutralization of reactive species, removal of misfolded proteins and damaged organelles, attenuation of inflammatory responses, and thus will maintain cellular homoeostasis and tissue integrity. Dr. Zhang's long-lasting interest in to understand the interplay between the Nrf2 and autophagy pathways and their roles in cancer, and to develop therapeutics targeting these two pathways for cancer prevention and intervention.
Dr. Zhang's laboratory has four major research projects. Each of these projects attempts to increase our understanding of how the Nrf2-mediatated antioxidant response is activated, and how to use this knowledge to identify/develop Nrf2-targeting compounds for disease intervention, thus improving human health. Also, visit Dr. Zhang's laboratory website.