There is a potential for self-repair after adult or neonatal stroke, but endogenous neurogenesis is short- lived and ineffective. Our goal is to enhance the repair after neonatal stroke. Angiogenesis facilitates neurogenesis after adult stroke through the formation of a "neurovascular niche." Brain macrophages can modulate repair and functional recovery after stroke through effects on the brain microenvironment and direct effects on angiogenesis and neurogenesis. Galectin-3 (Gal-3) has recently been implicated in the process of angiogenesis. The postulated ability of Gal-3 to provide a "docking point" for the formation of a neurovascular niche and to mediate VEGF-induced angiogenesis makes this molecule an attractive target for enhancing repair, but its effect on repair after neonatal stroke is not known. We hypothesize that microglia/macrophages critically affect long-term recovery after neonatal stroke, in part through enhanced Gal-3-dependent angiogenesis. Using our established models of transient middle cerebral artery occlusion in neonatal rats and mice, we wil determine whether angiogenesis and neurogenesis depend on Gal-3 produced in brain macrophages.
In Aim 1, we will determine the effects of microglial depletion on angiogenesis and neurovascular niche formation after neonatal stroke. We will monitor axonal outgrowth in living animals by bioluminescence.
In Aim 2, we will investigate the effects of enhanced or disrupted Gal-3 signaling on endothelial activation in living rats by ultrasound enhanced with specific molecular probes to target ?vss3 integrin. Repair will be further studied in neonatal ischemic Gal-3 knockout mice bearing the dual luc/gfp reporter under the TLR2 promoter.
In Aim 3, we will delineate neurovascular niche formation folowing Gal-3 or VEGFR2 inhibition in injured living rats by using ultrasound and specific probes for VEGFR2. VEGF-mediated angiogenesis will be determined in injured Gal-3 knockout mice. Functional consequences of microglial depletion and Gal-3 manipulations after neonatal stroke will be determined. Understanding the mechanisms regulating repair is an important first step on the way to successful bench-to-bed translation to enhance repair in injured newborn brains.

Public Health Relevance

Stroke in the term newborn occurs in 1 in 4000 live births. Most infants survive with significant long-term disabilities. Understanding how to enhance recovery from stroke is critical for alleviating the suffering of children and decreasing the enormous cost to families and society.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS076726-01A1
Application #
8371152
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$384,383
Indirect Cost
$129,777
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Chip, Sophorn; Fernández-López, David; Li, Fan et al. (2016) Genetic deletion of galectin-3 enhances neuroinflammation, affects microglial activation and contributes to sub-chronic injury in experimental neonatal focal stroke. Brain Behav Immun :
van Velthoven, Cindy T; Dzietko, Mark; Wendland, Michael F et al. (2016) Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. J Neurosci Res :
Fernández-López, David; Faustino, Joel; Klibanov, Alexander L et al. (2016) Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke. J Neurosci 36:2881-93
Li, Fan; Faustino, Joel; Woo, Moon-Sook et al. (2015) Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke. J Neurochem 135:445-52
Titomanlio, Luigi; Fernández-López, David; Manganozzi, Lucilla et al. (2015) Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models. Pediatr Neurol 52:566-84
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Fernández-López, David; Natarajan, Niranjana; Ashwal, Stephen et al. (2014) Mechanisms of perinatal arterial ischemic stroke. J Cereb Blood Flow Metab 34:921-32
van Velthoven, Cindy T J; Gonzalez, Fernando; Vexler, Zinaida S et al. (2014) Stem cells for neonatal stroke- the future is here. Front Cell Neurosci 8:207

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