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Harry Ischiropoulos, Ph.D.

RESEARCH INTERESTS

Oxidative stress, post-translational protein modifications and protein aggregation in neurodegenerative diseases. Non-invasive discovery and validation of disease biomarkers.

RESEARCH TECHNIQUES

Biochemical analysis of post-translational modifications; liquid chromatography-mass spectrometry; proteomics; nitric oxide detection; cell model systems of neuronal injury.

RESEARCH SUMMARY

A major effort in my laboratory has been directed towards the identification and quantification of proteins modified post-translationally by and oxidants in human diseases. Oxidative stress and most critically stress induced by reactive nitrogen species has been implicated as a common molecular pathway for the development of pathological phenotypes in a variety of human disorders. We discovered that selective nitration and oxidation of tyrosine residues is one of the major consequences of oxidative stress and formation of reactive nitrogen species. Proteins nitrated on tyrosine residues have been detected in all major organs in more than 60 human disorders.

Recent efforts include the use of proteomics to identify proteins that are nitrated in human diseases such as respiratory distress syndromes of neonates and adults, vascular and neurodegenerative disorders. Ongoing efforts have been focused on three specific proteins; a -synuclein, tyrosine hydroxylase and fibrinogen. Other studies utilizing proteomics and structure-function biochemical and biophysical approaches investigate the sites of tyrosine nitration and more critically the consequences of this modification on protein function. Moreover, the utility of tracking the changes in nitrated and oxidized plasma proteins as non-invasive predictors of disease development, disease outcome or as surrogate markers for determining the efficacy of therapeutic interventions is being evaluated in human populations.

We are also exploring the development of neuroprotective strategies by expressing in the brain proteins that resistant to oxidative stress and by generating cell lines adapted to reactive nitrogen species that are suitable for transplantation. Genomic and proteomic analyses are utilized to characterize the resistant cell lines. Finally, we are exploring the possibility of utilizing protein tyrosine nitration and oxidation to heighten immune responses and to augment the function of proteins in the coagulation cascade.

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