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NYU Reference Number- RON01-01
Background
Primary reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyl radicals
and superoxide radicals contribute to the pathogenesis of important human diseases
caused by neuronal ischemia during stroke, post-cardiopulmonary bypass syndrome,
and brain trauma. They have also been implicated in injuries associated with more
chronic diseases, including pancreatic damage during Diabetes Mellitus and neuronal
damage during Parkinson’s disease and other neurodegenerative disorders. To
combat the deleterious effects of ROS, cells have preconditioning responses in which
exposure to small doses of the stress causing substance activates genes that render
the cells resistant to future stress. The integrated stress response (ISR) is a signaling
pathway that responds to the stress caused by accumulation of malfolded protein in
the endoplasmic reticulum and cytoplasm and promotes such preconditioning. The identification
of compounds that activate this preconditioning response without placing stress on
cells could lead to therapeutics for diseases caused by accumulation of ROS.
Description of project
In response to small doses of stress, cells activate a signaling cascade that allows
them to defend against future encounters with the stress causing substance. The cascade,
which is activated by the accumulation of malfolded proteins in the ER, begins when
the kinase PERK phosphorylates the translational initiator, EIF2a. Phosphorylation
of EIF2a regulates stress-induced gene expression and is essential for cells to survive
exposure to conditions that promote protein malfolding in the ER. To date, identification
of compounds that cause this preconditioning response has been problematic, because
most potential therapeutics also cause stress on the cell. This assay enables screening
of compounds that activate expression of known target genes or proteins in the preconditioning
response. Furthermore, by monitoring IRE1 phosphorylation or GCN2 activation, which
are proteins activated by stress, it can eliminate potential therapeutic substances
that cause stress.
Application
The chief application of this technology is high throughput screening for compounds
that prevent or treat diseases caused by oxidative stress. Such therapeutic agents
could be efficacious in treating a wide range of diseases. The uses range from preventing
anticipated neurological damage associated with head trauma, cardio-pulmonary bypass
and the post-neurosurgery period to preventing renal damage induced by ischemia or
toxin exposure. Furthermore, identification of potential therapeutics may also be
useful for treating chronic diseases associated with cell and tissue damage caused
by ROS. Such conditions include Diabetes Mellitus, Parkinson’s Disease and
Cirrhosis.
Patent A patent has been filed
For further information please contact
New York University
Office of Industrial Liaison
650 First Avenue, New York, N.Y. 10016
Tel: (212) 263-8178 Fax: (212) 263-8189
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