Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Toll-Like Receptor (TLR) signaling can reprogram an inflammatory (injurious) response to stroke into a neuroprotective response in the brain. Agonists of TLRs 9 and 7 (CpG ODNs and imiquimod ?IMQ, respectively) are lead compounds for prophylactic neuroprotection against stroke. Clinical translational failures from rodent to human prompted additional preclinical evaluation. Using a primate stroke model we aim to establish essential effacy and pharmacokinetic data. Our preliminary studies support development of neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via:
Aim 1. Determine the optimal dose to achieve neuroprotective efficacy with TLR9 (K-and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke.
Aim 2. Determine the time window of neuroprotective efficacy for the optimal drug in male NHP stroke model.
Aim 3. Determine neuroprotective efficacy as prophylactic therapy in aged NHP.
Aim 4. Determine the neuroprotective efficacy of repeated in a NHP model of cortical stroke.
Aim 5. Determine the neuroprotective efficacy of the optimal drug as prophylactic stroke therapy in female NHPs.
Aim 6. Determine pharmacokinetic and toxicity profiles.
Aim 7. Submit an IND application for the optimal candidate based on efficacy, pharmacokinetics and toxicity. Progress:
Aim 1 studies are near completion, although the blinded study design, while optimal, prevents any preliminary analysis of the data collected so far.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000163-52
Application #
8357838
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
52
Fiscal Year
2011
Total Cost
$58,239
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Okoye, Afam A; Hansen, Scott G; Vaidya, Mukta et al. (2018) Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat Med 24:1430-1440
Jensen, Jeffrey T; Hanna, Carol; Mishler, Emily et al. (2018) Effect of menstrual cycle phase and hormonal treatments on evaluation of tubal patency in baboons. J Med Primatol 47:40-45
Toro, C A; Aylwin, C F; Lomniczi, A (2018) Hypothalamic epigenetics driving female puberty. J Neuroendocrinol 30:e12589
Bulgarelli, Daiane L; Ting, Alison Y; Gordon, Brenda J et al. (2018) Development of macaque secondary follicles exposed to neutral red prior to 3-dimensional culture. J Assist Reprod Genet 35:71-79
Prola-Netto, Joao; Woods, Mark; Roberts, Victoria H J et al. (2018) Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure. Radiology 286:122-128
Moccetti, Federico; Brown, Eran; Xie, Aris et al. (2018) Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries. J Am Coll Cardiol 72:1015-1026
Blue, Steven W; Winchell, Andrea J; Kaucher, Amy V et al. (2018) Simultaneous quantitation of multiple contraceptive hormones in human serum by LC-MS/MS. Contraception 97:363-369
Jeon, Sookyoung; Li, Qiyao; Rubakhin, Stanislav S et al. (2018) 13C-lutein is differentially distributed in tissues of an adult female rhesus macaque following a single oral administration: a pilot study. Nutr Res :
Slayden, Ov Daniel; Friason, Francis Kathryn E; Bond, Kise Rosen et al. (2018) Hormonal regulation of oviductal glycoprotein 1 (OVGP1; MUC9) in the rhesus macaque cervix. J Med Primatol 47:362-370
Dissen, G A; Adachi, K; Lomniczi, A et al. (2017) Engineering a gene silencing viral construct that targets the cat hypothalamus to induce permanent sterility: An update. Reprod Domest Anim 52 Suppl 2:354-358

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