This grant focuses on translational research to advance neuroimaging techniques that will enhance the potential of human neural stem cell (hNSC) implantation to treat neonatal hypoxic- ischemic brain injury (HII). Our goal is to use advanced magnetic resonance imaging (MRI) in a standard rat pup model of unilateral middle cerebral artery occlusion with hypoxia (Rice- Vannucci, RVM) to: (1) monitor non-invasively (as might be done clinically) hNSC migration, proliferation, location and as an outcome biomarker;(2) use imaging to tailor optimal implantation (site, dose, and timing);and (3) develop candidate selection criteria based on imaging model injury severity. Using an 11.7T MRI, we have developed: (1) a automated 3D MRI volumetric method to measure total and regional HII volumes;(2) a MRI based Rat Pup Scoring System (RPSS);(3) a 3-tiered model of HII severity (mild, moderate, severe) based on 3D HI volumes and the RPSS;and (4) 3 quantifiable neuroimaging parameters (migration, proliferation and final location) using Feridex-labeled hNSCs that can be compared with 4 quantifiable histological, immunohistochemistry and neurophysiological parameters of hNSC fate (integration, differentiation, connectivity, and survival). These data will be evaluated at 3 months against an extensive battery of behavioral testing.
Aim 1 a will examine whether neuroimaging parameters correlate with parameters of hNSC fate.
Aim 1 b will examine if iron labeling adversely affects NSCs or causes additional tissue injury.
Aim 2 will assess the efficacy of neuroimaging to determine site, dose, and timing of implantation for optimal structural and metabolic recovery.
Aim 3 will use neuroimaging to examine whether the ability of hNSCs to improve structural, metabolic and behavioral outcomes depends upon the severity of the initial HII using the RVM and a new model of bilateral injury (bilateral carotid occlusion with hypoxia;BCAO-H). This grant addresses many of the important technical and biological issues that must be considered in order to improve the chance for success of NSC therapy. By using advanced imaging methods to determine HII severity, injury location and injury volumes, we have developed a unique and objective approach to evaluate efficacy of hNSC implantation. hNSC treatment is an extremely promising approach to treat HII, but we have an obligation to provide the scientific foundation in a careful, objective, logical and safe manner before embarking on clinical trials in newborns.

Public Health Relevance

This grant focuses on translational research to advance neuroimaging techniques that will enhance the potential of human neural stem cell (hNSC) implantation to treat neonatal hypoxic- ischemic brain injury (HII). Our goals are to use advanced magnetic resonance imaging (MRI) techniques as an outcome measure and to: (1) monitor non-invasively (as might be done clinically) hNSC migration, proliferation and location;(2) optimize hNSC implantation site, dose, and timing;and (3) identify potential therapeutic candidates based on early MRI measures of injury severity. Using an 11.7T MRI in two models ischemia and hypoxia we have developed automated 3D MRI volumetric methods to measure total and regional HII volumes and NSC migration. This proposal will have a significant impact on treating neonatal HII with hNSCs. Development of automated MRI methods that objectively quantify injury, confirm precision of implantation, monitor hNSC activity, and quantify brain volumetric recovery is critical for translational research as a prelude to trials in higher order species and then clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059770-04
Application #
8230530
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Owens, David F
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$315,878
Indirect Cost
$68,229
Name
Loma Linda University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
Ghosh, Nirmalya; Sun, Yu; Bhanu, Bir et al. (2014) Automated detection of brain abnormalities in neonatal hypoxia ischemic injury from MR images. Med Image Anal 18:1059-69
Ashwal, Stephen; Ghosh, Nirmalya; Turenius, Christine I et al. (2014) Reparative effects of neural stem cells in neonatal rats with hypoxic-ischemic injury are not influenced by host sex. Pediatr Res 75:603-11
Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian et al. (2014) Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage. ASN Neuro 6:
Obenaus, Andre; Dilmac, Nejmi; Tone, Beatriz et al. (2011) Long-term magnetic resonance imaging of stem cells in neonatal ischemic injury. Ann Neurol 69:282-91
Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society; Delgado, M R; Hirtz, D et al. (2010) Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology 74:336-43
Graf, W D; Le Pichon, J-B; Bittel, D C et al. (2010) Practice parameter: evaluation of the child with microcephaly (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 74:1080-1; author reply 1081
Ashwal, Stephen; Michelson, David; Plawner, Lauren et al. (2009) Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 73:887-97