This study is designed to identify changes in the blood, both genomic and proteomic, which may be predictive of successful prophylactic neuroprotection with CpG ODNs (unmethylated cytosine-guanosine rich oligodeoxynucleotides). This approach involves preconditioning through Toll-like receptor (TLR) activation as a robust prophylactic treatment for patients at high risk of ischemic brain injury. Prophylactic neuroprotection of high risk populations has the potential to protect patients from devastating neurological complications and death. This work is based on the endogenous neuroprotective phenomenon of ischemic tolerance, which preconditions the brain against subsequent ischemic injury. TLRs are a family innate immune receptors for pathogen-associated molecules (e.g. bacterial lipopolysaccharide, bacterial DNA, single stranded RNA). TLR9, and its agonist, CpG ODNs, is a new therapeutic candidate for neuroprotection that has been validated extensively in rodent-based models of ischemic injury. Additionally, CpG ODNs show good safety and tolerability in phase I/II/III clinical studies in man. RNA and serum samples collected from a study of CpG-induced neuroprotection in a novel model of cortical stroke in the rhesus macaque will be used for the genomic and proteomic studies outlined in this proposal. Analysis of genomic and proteomic changes in blood may lead insight into the mechanism by which these agents induce neuroprotection. Further, identification of systemic biomarkers would provide critical information for future clinical trial with CpG ODNs that would involve patients who are at risk of brain ischemia.

Public Health Relevance

This study is designed to identify changes in the blood which may be predictive of successful prophylactic neuroprotection with CpG ODNs (unmethylated cytosine-guanosine rich oligodeoxynucleotides). Analysis of genomic and proteomic changes in blood may lead insight into the mechanism by which these agents induce neuroprotection. Further, identification of systemic biomarkers would provide critical information for future clinical trial with CpG ODNs that would involve patients who are at risk of brain ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS070359-04
Application #
8450126
Study Section
NST-2 Subcommittee (NST)
Program Officer
Whittemore, Vicky R
Project Start
2010-04-01
Project End
2014-12-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Williams-Karnesky, Rebecca L; Sandau, Ursula S; Lusardi, Theresa A et al. (2013) Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest 123:3552-63