Molecular Recognition in Biological Systems and Bioinformatics

Inhibition of CNTF-induced STAT3-EGFP nuclear translocation in BE(2)-C Cells after hydrogen peroxide or cadmium chloride.

Oxidative stress; neuropharmacology; neurodegenerative disorders; signal transduction.

A number of neurodegenerative diseases are associated with increased oxidative stress in nerve cells. These include Parkinson's Disease, amyotrophic lateral sclerosis, Huntington's Disease and Alzheimer's Disease. The sources of oxidative stress in nerve cells is of considerable importance for understanding disease progression and in developing effective therapies. Environmental contaminants have emerged as an area of increasing interest as possible contributing factors in disease progression. Exposure to metals such as cadmium (Cd) and mercury (Hg) and certain toxins (e.g. rotenone) cause serious neurological disorders. However, the cellular mechanisms of these metals and their impacts on neural diseases are not well understood. Our recent work suggests that oxidative stress disrupts signaling for key neurotrophic factors selectively in nerve cells.

Nerve cells require continuous trophic support to develop and survive and thus neurotrophic factors are potential therapeutic agents for neurodegenerative disease. An important group of factors is the ciliary neurotrophic factor (CNTF) family of factors. These factors require the Jak/STAT signal transduction network for its effects. We have found that Cd and Hg, by producing oxidative stress in cells, can completely ablate Jak/STAT signaling in nerve cells. Our working hypothesis is that the neurotoxicity of these metals is due at least in part to the oxidative modification of specific amino acids in Jak proteins. These studies will define new molecular mechanisms regulating Jak/STAT signaling in nerve cells and provide new information on the potential roles of environmental metal toxicants in the etiology and progression of neurological diseases.

Chicken embryo

• Jak tyrosine kinases
• STAT transcription factors
• Ciliary neurotrophic factor (CNTF)
• Cytokines

• Neurodegenerative diseases
• Cadmium toxicity
• Mercury toxicity

• Western blotting
• Immunofluorescence
• Cell transfection
• EMSA

• Phospho-specific antibodies
• STAT-EGFP plasmids
• Jak kinase expression plasmids
• SOD mutant plasmids

• BE-2C human neuroblastoma
• HepG2 liver
• SH-SY5Y human neuroblastoma
• Chick ciliary ganglia, DRG
• HMN-1 motor neuron

Neurodegenerative diseases, aging, neurotoxicity from environmental agents, heavy metal poisoning.

Nervous system

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