: The overall aim of this application is to elucidate the biochemical events leading from PARP and PARG activation to cell death, and to investigate potential interventions that could abrogate this cell death. Poly (ADP-ribose) polymerase-1 (PARP1) generates ADP-ribose polymers on many target proteins when activated by single-strand DNA breaks. PARP 1 is now well established as a mediator of cell death under conditions that lead to extensive or sustained activation. In particular, PARP1 gene disruption and PARP inhibitors have been shown to reduce brain infarction after cerebral ischemia. However, the intervening biochemical steps between PARP activation and cell death are not well understood. Our preliminary results and previously published reports suggest the involvement of secondary oxidative stress and impaired substrate delivery to mitochondria as key intermediate steps in PARP 1-mediated cell death. Providing cells with antioxidants or with TCA cycle substrates at time points after PARP 1 activation improves cell survival. Poly(ADP-ribose) glycohydrolase (PARG) binds to the (ADP-ribose) polymers produced by PARP1 and rapidly hydrolyzes them to mono(ADP-ribose). Our preliminary results also suggest that PARG is of equal importance as PARP1 in mediating oxidative and excitotoxic cell death. The studies proposed will employ cortical cultures from wild type and PARP-/- mice, neuroblastoma cells, and a mouse model of cerebral ischemia to investigate the biochemical mechanisms by which PARP and PARG activation lead to cell death. These studies will also explore interventions for reducing cell death at time points after PARP 1 activation. A better understanding of these processes could lead to neuroprotective approaches aimed at downstream events in the evolution of cell death after ischemia and other insults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS041421-01A1
Application #
6434139
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Behar, Toby
Project Start
2001-12-15
Project End
2005-11-30
Budget Start
2001-12-15
Budget End
2002-11-30
Support Year
1
Fiscal Year
2002
Total Cost
$342,238
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Shen, Yiguo; Kapfhamer, David; Minnella, Angela M et al. (2017) Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP. Nat Commun 8:624
Reyes, Reno C; Cittolin-Santos, Giordano Fabricio; Kim, Ji-Eun et al. (2016) Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid. Neurotherapeutics 13:217-25
Vuong, Billy; Hogan-Cann, Adam D J; Alano, Conrad C et al. (2015) NF-?B transcriptional activation by TNF? requires phospholipase C, extracellular signal-regulated kinase 2 and poly(ADP-ribose) polymerase-1. J Neuroinflammation 12:229
Sheth, Sunil A; Iavarone, Anthony T; Liebeskind, David S et al. (2015) Targeted Lipid Profiling Discovers Plasma Biomarkers of Acute Brain Injury. PLoS One 10:e0129735
Jain, Mohit; Ngoy, Soeun; Sheth, Sunil A et al. (2014) A systematic survey of lipids across mouse tissues. Am J Physiol Endocrinol Metab 306:E854-68
Swanson, Raymond A (2014) Glucose, acid, and aspartate: Friends and foes of the axon. Ann Neurol 75:490-1
Chen, Y; Won, S J; Xu, Y et al. (2014) Targeting microglial activation in stroke therapy: pharmacological tools and gender effects. Curr Med Chem 21:2146-55
Robbins, Nathaniel M; Swanson, Raymond A (2014) Opposing effects of glucose on stroke and reperfusion injury: acidosis, oxidative stress, and energy metabolism. Stroke 45:1881-6
Baxter, Paul; Chen, Yanting; Xu, Yun et al. (2014) Mitochondrial dysfunction induced by nuclear poly(ADP-ribose) polymerase-1: a treatable cause of cell death in stroke. Transl Stroke Res 5:136-44
Cleaver, James E; Brennan-Minnella, Angela M; Swanson, Raymond A et al. (2014) Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage. Proc Natl Acad Sci U S A 111:13487-92

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