The overall goal of this project is to understand the role of poly(ADP-ribose) in the pathogenesis and pathology of neuronal injury following excitotoxicity and ischemia-reperfusion injury. The Program represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complimentary areas of expertise who have a long-term commitment to studies of neuronal injury. This Program will integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contribution than could be achieved if each project were pursued individually. The Program has two themes: first, to understand the cell biology and biochemistry of poly(ADP-ribose) as a signaling molecule which results in neuronal damage. Wild-type and mutant mice will be used to the actions of poly(ADP-ribose) and to determine the cellular targets of poly(ADP-ribose) activity that trigger neuronal cell death. Second, the actions of apoptosis inducing factor and endonuclease G as downstream mediators of PAR dependent cell death, will be explored using molecular biologic, cell biologic and pathologic experiments. State of the art molecular, cellular, neuropathological, physiological and proteomic approaches are used throughout the Program. The Program has several important strengths. The investigators have a history of interactive studies of neuronal injury and mechanisms to limit injury in the nervous system. The investigators are leaders in the field of neuronal injury and ischemia. Sophisticated experimental approaches are used to gain insight into this novel mediator of neuronal death. We believe that our multi-disciplinary approach has the capacity to produce unique information conceming the mechanism of neuronal injury mediated by poly(ADP-ribose) and translocation of apoptosis inducing factor to hopefully determine new therapeutic opportunities to capitalize on the observation of profound neuroprotection observed in the poly(ADP-ribose) polymerase knockout mice. The Program consists of three projects and two cores: 1) Apoptosis Inducing Factor in Neuronal Injury, 2) Poly(ADP-ribose) Signaling in Glutamate Excitotoxicity, 3) Molecular Mechanisms of PARP-Dependent Cell Death in Stroke, A) Administrative Core, B) Gene Expression Core.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS039148-08
Application #
7099421
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Golanov, Eugene V
Project Start
1999-08-06
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
8
Fiscal Year
2006
Total Cost
$1,374,164
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Wang, Yingfei; Kim, No Soo; Haince, Jean-Francois et al. (2011) Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci Signal 4:ra20
Andrabi, Shaida A; Kang, Ho Chul; Haince, Jean-Fran├žois et al. (2011) Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nat Med 17:692-9
Kang, Ho Chul; Lee, Yun-Il; Shin, Joo-Ho et al. (2011) Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. Proc Natl Acad Sci U S A 108:14103-8
Li, Xiaoling; Klaus, Judith A; Zhang, Jian et al. (2010) Contributions of poly(ADP-ribose) polymerase-1 and -2 to nuclear translocation of apoptosis-inducing factor and injury from focal cerebral ischemia. J Neurochem 113:1012-22
Xu, Zhenfeng; Zhang, Jian; David, Karen K et al. (2010) Endonuclease G does not play an obligatory role in poly(ADP-ribose) polymerase-dependent cell death after transient focal cerebral ischemia. Am J Physiol Regul Integr Comp Physiol 299:R215-21
Kishimoto, Koji; Li, Rung-Chi; Zhang, Jian et al. (2010) Cytosolic phospholipase A2 alpha amplifies early cyclooxygenase-2 expression, oxidative stress and MAP kinase phosphorylation after cerebral ischemia in mice. J Neuroinflammation 7:42
Wang, Yingfei; Kim, No S; Li, Xiaoling et al. (2009) Calpain activation is not required for AIF translocation in PARP-1-dependent cell death (parthanatos). J Neurochem 110:687-96
Yu, Seong-Woon; Wang, Yingfei; Frydenlund, Didrik S et al. (2009) Outer mitochondrial membrane localization of apoptosis-inducing factor: mechanistic implications for release. ASN Neuro 1:
Wang, Yingfei; Dawson, Valina L; Dawson, Ted M (2009) Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 218:193-202

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