Li Zhang, Ph.D.,
Professor of Environmental Health Sciences
(effective July 1, 2004)

Dr. Zhang's research focuses on oxygen sensing, heme signaling and molecular actions of environmental neurotoxicants. Oxygen is central to the survival and development of many living organisms, including humans. The human brain requires continuous supply of oxygen and consumes 20% of the body's oxygen. Heme is central to oxygen sensing and utilization in living organisms. Defects in oxygen sensing and heme signaling in humans cause serious diseases, including cancers, neurological and hematological diseases. Notably, defective heme synthesis can cause a wide array of neurological disorders associated with both CNS and peripheral nervous systems. For example, lead-induced encephalopathy may be caused, at least in part, by its inhibition of the activity of, 5-aminolevulinic acid dehydratase, an enzyme involved in heme biosynthesis. Altered heme metabolism is also associated with schizophrenia.

Our research goal is to decipher the molecular events underlying numerous diseases associated with oxygen sensing, heme signaling, and environmental neurotoxicants. To this end, we perform experiments in three areas:

1. Molecular actions of neurotoxicants. Human neuronal and glial cells are used to investigate how environmental neurotoxicants, including metals and pesticides, may alter cellular signaling, gene expression and cell survival in the human brain.

2. Molecular mechanisms of oxygen sensing and heme action in neuronal cells. Mammalian neuronal cells are used to identify and characterize the pathways and genes involved in oxygen sensing and those altered by changing intracellular heme levels.

3. Molecular mechanisms of oxygen sensing and heme signaling in yeast. Yeast is used as a model system to investigate the oxygen sensing and heme signaling network in eukaryotes. Results from yeast studies should provide insights into how oxygen is sensed in higher eukaryotes, including humans.

Selected Publications:

Ye WZ, Zhang L*. 2004. Heme controls the expression of cell cycle regulators and cell proliferation in HeLa Cells. Biochem Biophys Res Commun 315: 546-54.

Lee HC, Hon T, Lan C, Zhang L*. 2003. Structural Environment Dictates the Biological Significance of Heme-responsive Motifs and the Role of Hsp90 in the Activation of the Heme Activator Protein Hap1. Mol Cell Biol 23: 5857-66.

Hon T, Dodd A, Dirmeier R, Gorman N, Sinclair PR, Zhang L*, Poyton RO. 2003. A Mechanism of Oxygen Sensing in Yeast: Multiple Oxygen-Responsive Steps in the Heme Biosynthetic Pathway Affect Hap1 activity. J Biol Chem 278:50771-80.

Zhu Y, Lee HC, Zhang L*. 2002. An Examination of Heme Action in Gene Expression: Heme and Heme Deficiency Affect the Expression of Diverse Genes in Erythroid K562 and Neuronal PC12 cells. DNA and Cell Biology 21: 333-46.

Lee HC, Hon T, Zhang L*. 2002. The Hsp90 molecular chaperone mediates heme activation of the yeast transcriptional activator Hap1. J Biol Chem 277: 7430-7.

Zhu Y, Hon T, Ye WZ, Zhang L*. 2002. Heme Deficiency Selectively Interferes with the Ras-MAPK Signaling Pathway and the Expression of a Subset of Neuronal Genes. Cell Grow. & Diff. 13: 431-9.

Hon T, Lee HC, Hach A, Johnson JL, Craig EA, Erdjument-Bromage H, Tempst P, Zhang L*. 2001. The Hsp70-Ydj1 Molecular Chaperone Represses the Activity of the Transcriptional Activator Hap1 in the Absence of Heme. Mol Cell Biol 21: 7923-32.

Zhang L*, Hach A. 1999. Molecular mechanism of heme signaling in yeast: The transcriptional activator Hap1 serves as the key mediator. Cell Mol Life Sci 56: 415-26.