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Neuropathology Research Projects

Grafe:

Role of DNA damage response in perinatal hypoxia-ischemia. PI: Marjorie Grafe, MD, PhD

This project is part of a Program Project Grant focusing on mechanisms of cell death after perinatal ischemic brain injury in a rodent model. Our current focus is on the effects of post-hypoxic treatment with 100% or 40% oxygen, as compared to room air. We have recently demonstrated that long term histological outcome (6 weeks) was no different in animals who were given 2 hours of post-hypoxia 100% oxygen as compared to room air. Both short term and long term behavioral studies are underway.

Martin SS, Perez-Polo JR, Noppens KM, Grafe MR. Biphasic changes in the levels of poly(ADP-ribose) polymerase and caspase 3 in the immature brain following hypoxia-ischemia. Int J Devel Neurosci 23:673-686, 2005.

Grafe MR, Woodworth KN, Noppens K, Perez-Polo JR. Long-term histological outcome after post-hypoxic treatment with 100% or 40% oxygen in a model of perinatal hypoxic-ischemic brain injury. International Journal of Developmental Neuroscience. doi:10.1016/j.ijdevneu.2007.09.004

Soluble epoxide hydrolase as a novel therapeutic target of stroke. PI: Nabil Alkayed, PhD (OHSU Dept. of Anesthesiology)

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). This study examines the role of soluble epoxide hydrolase (sEH) in ischemic neuronal injury, and the potential utility of sEH inhibitors as neuroprotective agents in stroke. The findings suggest that she inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke.

Zhang W, Koerner IP, Noppens R, Grafe M, Tsai H-J, Morisseau C, Luria A, Hammock BD, Falck JR, Alkayed NJ. Soluble epoxide hydrolsae: a novel therapeutic target in stroke. J Cerebral Blood Flow Metab, advance online publication 18 April 2007; doi:10.1038/sj.jcbfm.9600494.

Role of extracellular matrix in hypoxic-ischemic perinatal white matter injury. PI: Stephen Back, M.D., Ph.D. (OHSU Dept. of Pediatrics)

This study examines mechanisms by which acute white matter injury disrupts normal myelinogenesis, specifically by testing the hypothesis that acute degeneration of oligodendrocyte precursors trigger reactive astrocytosis and accumulation of hyaluronan and that hyaluronan blocks maturation of oligodendrocyte precursors.

Mechanisms of Regulation of Cerebral Blood Flow. PI: Richard Traystman, Ph.D. (OHSU Dept. of Anesthesiology)

The overall goal of this Program Project is to define mechanisms of neuronal injury following focal and global cerebral ischemic in adult and pediatric animals. I supervise a neuropathology core that serves all projects in this PPG.

Kofler J, Otsuka T, Zhang Z, Noppens R, Grafe MR, Koh DW, Dawson VL, de Murcia JM, Hurn PD, Traystman RJ. Differential effect of PARP-2 deletion on brain injury after focal and global cerebral ischemia. J Cerebral Blood Flow Metab 26:135-41, 2006.

Sudden Unexpected Death in Childhood. PI: Henry Krous, MD, Rady Children’s Hospital, San Diego, Director, The San Diego SIDS/SUDC Research Project.

Since mid-2006, I have served as the neuropathologist for this study. The purposes of this research include:

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