Baylor College of Medicine
Houston, TX, US
Nancy Chang, Ph.D. Endowed Chair for the Biology of Inflammation Center
Baylor College of Medicine
Houston, Texas, United States
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States

Professional Interests

  • Regulation of Autophagy in Innate Immunity
  • Cellular Regulation of Nitric Oxide Synthesis in Inflammation
  • Cellular regulation of misfolded proteins

Professional Statement

Our laboratory is interested in three related aspects of the molecular cell biology mechanisms of inflammation. These are: the process of elimination of pathogens by autophagy and the regulation of nitric oxide synthesis by inducible nitric oxide synthase (iNOS) and cellular regulation of misfolded proteins.

Regulation of Autophagy in Innate Immunity

Our work on autophagy involves determining the molecular pathways regulating autophagy during pathogen infection. Autophagy has been recently shown to be an important component of the innate immune response by degrading foreign microbial invaders. The upstream signaling pathways leading to activation of autophagy are not known and currently under investigation in our laboratory. Our recent study links autophagy to innate immunity Toll-like receptor 4 (TLR4). Further, it defines the signaling pathway downstream from TLR4 via TRIF/RIP1/p38MAPK. This pathway maintains cell survival in the context of autophagy associated with infection and is distinct from autophagic cell death. The potential therapeutic use of modulating this pathway is significant. As a proof of concept, we used LPS treatment to force mycobacterium tuberculosis to the autophagosomes and to be lysed by the lysosomes.

Cellular Regulation of Nitric Oxide Synthesis in Inflammation

Our laboratory is credited with several key discoveries for the regulation of iNOS. These discoveries included regulation of iNOS by alternative mRNA splicing, elucidation of structural domains required for iNOS activity and dimerization, determination of key residues in iNOS structure needed to control its activity and substrate binding, identifying the degradation pathway for iNOS, elucidating iNOS regulation by ubiquitination, determining the rate of cellular iNOS turnover and discovering the translational inhibition of iNOS by dimerization inhibitors. In addition, we have recently shown that iNOS forms what we termed the ‘physiologic aggresome”. Previously the aggresome has been thought to represent a sequestration of misfolded proteins. Thus, iNOS aggresome defines a new paradigm for cellular regulation of protein processing. This extensive work on the mechanisms of iNOS regulation has increased our understanding of iNOS biology and has laid the ground work for potential breakthroughs both in understanding iNOS regulation as well in devising novel strategies to regulate iNOS in diseases characterized by over production of NO. The work on iNOS extends our observations to how cells regulate protein trafficking between the proteasome (for degradation) and the aggresome (as a holding station). Thus, the significance of the work involves many pathological conditions including lung inflammation and fibrosis, cardiovascular shock, and stroke and neurodegenerative diseases.

Cellular Regulation of misfolded proteins

Our work with both autophagy and iNOS has revealed several important insights into how cells regulate protein trafficking and homeostasis under physiologic and pathologic conditions. Current projects on our laboratory focus on signaling pathway and regulatory proteins that regulate these processes. Specifically, we would like to determine how cells switch proteins among proteasome, aggresome and autophagy pathways. In addition, we are studying various cellular responses and consequences of the presence of misfolded proteins known to associate with human diseases such as in cystic fibrosis and alpha-1 antitrypsin related diseases.

Selected Publications