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Research Labs
 Michael R. Chicoine, M.D.Ralph G. Dacey, M.D., and
Hans Dietrich, Ph.D.Jeffrey M. Gidday, Ph.D., and
T.S. Park, M.D.Eric Leuthardt MDKeith M. Rich, M.D.Matthew D. Smyth,
MD, FACS, FAAP
Thomas A. Woolsey, M.D.Gregory J. Zipfel M.D. and
Henry Han Ph.D.
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Department of Neurosurgery
Washington University
School of Medicine
Campus Box 8057
660 S. Euclid Ave.
St. Louis, MO 63110
(314) 362-3577 |
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Principal Investigators
Jeffrey M. Gidday Ph.D.
T. S. Park, M.D.
Lab Personnel
Yanli Zhu, M.D.
Ann M. Stowe Ph.D.
Bradley K. Wacker D.Sc.
Lihong Zhang, MS.
Angie Freie, BS
Jennifer Perfater, BS
Ruilong Hu (undergraduate)
Robbie Gilchrist (undergraduate)
Research in our laboratory is aimed at elucidating the mechanisms responsible for the promotion of robust neuronal and vascular protection against ischemic injury in CNS tissues (a phenotype called “ischemic tolerance”) in response to sublethal hypoxic “preconditioning” stress. (See Gidday, Nat. Neurosci. Rev. 7: 437, 2006 for a recent review). Our current focus is on vascular mechanisms of ischemic tolerance and anti-inflammatory responses that may underlie it. We also investigate the molecular mechanisms of vascular dysfunction in brain and retina in response to ischemia. Our studies employ videomicroscopic methods in transgenic mice and other animals to directly visualize oxidative (oxygen and nitrogen radicals), inflammatory (polymorphonuclear leukocytes), and proteolytic (matrix metalloproteinases and neutrophilic proteases) injury processes in the CNS microcirculation. Cerebral endothelial cell cultures are also used concomitantly as an in vitro model of microvascular injury and protection. In short, our research program is focused on:
- the molecular and genetic basis of CNS protection from ischemia by hypoxic preconditioning
- anti-inflammatory and anti-apoptotic mechanisms operative in CNS ischemic tolerance
- vascular mechanisms of ischemic tolerance in brain
- oxidative, inflammatory, and proteolytic mechanisms regulating ischemia-induced neutrophil-endothelial interactions and blood-brain barrier dysfunction in the cerebral microcirculation
Recent Findings
- Role of eNOS and nNOS in cerebral inflammatory response to episodic hypoxia elucidated. J. Appl. Physiol. 96: 1223-1230, 2004.
- Apoptosis inducing factor (AIF) and poly(ADP-ribose)polymerase (PARP) implicated in ischemic cell death of cerebral endothelium. J. Cereb. Blood Flow Metab 25: 866-877, 2005.
- Neutrophil-derived MMP-9 identified as mediator of vasogenic edema and contributor to blood-brain barrier breakdown following transient focal stroke. Am. J. Physiol. 289: H558-568, 2005.
- NO from constitutive NOS isoforms participates in mediating retinal ischemic tolerance following ischemic preconditioning. Exp. Eye Res. 82: 153-163, 2006.
- Activation of pAkt and survivin protects preconditioned cerebral endothelial cells from apoptotic cell death following ischemia. Am. J. Physiol. 292: H2573-H2581, 2007.
- Repetitive hypoxic preconditioning provides long-lasting protection against retinal ischemia in a mechanism that involves HIF-1a and HO-1. Invest. Ophthalmol. Vis. Sci. 48: 1735-1743, 2007.
- Cerebrovascular inflammation and neuronal injury following global ischemia modulated by novel anti-chemotactic factor. Exp. Neurol. 207: 186-194, 2007.
- Sustained protection from retinal ischemic injury by preconditioning with desferroxamine. J Ocular Pharmacol Therap 24: 527-535, 2008.
- Neutrophil elastase mediates vascular and neuronal injury following stroke. Neurobiol Dis 35: 82-90, 2009.
- Activation of microvascular sphingosine kinase isoform essential to protection of stroked brain by hypoxic preconditioning. Stroke 40: 3342-3348, 2009
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Current Projects
Vascular Mechanisms of Cerebral Ischemic Tolerance
RO1 NHLBI HL79278-02, 7/1/05 - 6/30/10
The goal of this project is to elucidate the mechanisms responsible for cerebral endothelial cell protection from ischemic injury following hypoxic preconditioning, with a focus on the role of eNOS, HIF-2alpha, and survivin.
Ischemic Tolerance and Endothelial Protection
PO1 NS032636-13 "Cell-Cell Interactions and Hypoxic Brain Injury" (Program Project)
The major goals of Project 1 on this program project are to characterize the ischemia-tolerant phenotype at the level of the enothelial-blood interface in a model of long-term cerebral ischemic tolerance, with a focus on endothelial-neutrophil adherence, blood-brain barrier breakdown, and proinflammatory cytokine-chemokine signaling.
Endogenous Neuroprotection in Glaucoma
RO1 NEI EY018607, 2/1/08 – 1/31/12
The goals of this project are to uncover the induction and expression mechanisms that promote protection of retinal ganglion cells from glaucomatous apoptotic cell death by repetitive hypoxic preconditioning prior to disease onset. |
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