Grant Could Lead to Medical Breakthrough

Wulf Paschen, PhD, professor of anesthesiology in the Division of Basic Sciences, received a three-year $1,043,439 National Institutes of Health grant (R01) from the National Institute of Neurological Disorders and Stroke (NINDS) for his research project, titled “Effect of Age on Brain Ischemia/Stroke Outcome; Pathways, Mechanisms, and Rescue.” The goal of the project is to develop a novel strategy for neuroprotection, tailored specifically for elderly patients suffering from brain ischemia/stroke, to improve functional recovery. Working with Dr. Paschen on the project are co-investigators Drs. Wei Yang and Huaxin Sheng (Department of Anesthesiology), and Ivan Spasojevic (director of the PK/PD Core Laboratory), and significant contributors Drs. Dave Warner (Department of Anesthesiology) and John Chatham (University of Alabama at Birmingham).

Brain ischemia, induced by cardiac arrest or stroke, is a serious medical condition that affects more than one million people in the United States each year. The high incidence of brain ischemia-induced disability presents a major burden on families and health care systems. Dr. Paschen believe this problem will become even more serious as our population ages because age is the key risk factor for cardiac arrest and ischemic stroke. Thus, there is an urgent need to define the role of age in brain ischemia/stroke outcome in order to develop novel therapeutic strategies tailored for elderly patients.

Brain ischemia/stroke activates a variety of pathological processes that are believed to contribute to outcome. Traditionally, interfering with these pathological pathways has been exploited as therapeutic strategy. However, according to Dr. Paschen, all clinical trials based on this strategy have produced disappointing results. The Paschen group proposes a novel approach to neuroprotection that boosts an endogenous pro-survival pathway.

“Nature has perfected these stress-response pathways over a long period of evolution, and they are highly conserved, implying that they represent optimal strategies to protect cells from damage triggered by stress. Nature’s overarching strategy is to activate protective pathways that facilitate recovery of cellular functions impaired by stress, not to interfere with pathological processes triggered by stress,” says Dr. Paschen. “This suggests that a better strategy for neuroprotection after brain ischemia/stroke may be to boost a pro-survival pathway.”

Based on results recently published by the Paschen group, the project will focus on the unfolded protein response and downstream pathways with particular emphasis on O-linked b-N-acetylglucosamine (O-GlcNAc) modification of proteins, a pro-survival pathway in a variety of stress conditions. “We expect that our novel strategy to neuroprotection, specifically tailored to increase the resistance of aged brains to an ischemic challenge, could be a major breakthrough toward improving outcomes in elderly patients after an ischemic event,” add Dr. Paschen.

His enthusiasm is shared by the NOMD Review Group at NINDS which considered the strengths of the application to include the outstanding laboratory, the exciting potential of stimulating endogenous protective mechanisms to treat stroke rather than inhibiting injury pathways, and the potential use of this treatment post event. The application was, therefore, highly rated (six percentile) in the first submission cycle, and funding will begin in July.