Macrophages as modulators of repair after neonatal stroke

Summary

Principal Investigator: Zinaida Vexler
Abstract: DESCRIPTION (provided by applicant): 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 [unreadable]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.
Funding Period: 2012-07-01 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke
    Cindy T J van Velthoven
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
    Stroke 44:1426-32. 2013
  2. pmc Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke
    M Dzietko
    Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
    Transl Stroke Res 4:189-200. 2013

Research Grants

Detail Information

Publications2

  1. pmc Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke
    Cindy T J van Velthoven
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
    Stroke 44:1426-32. 2013
    ..We investigated whether MSC treatment improves recovery after neonatal stroke and whether MSC overexpressing brain-derived neurotrophic factor (MSC-BDNF) further enhances recovery...
  2. pmc Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke
    M Dzietko
    Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
    Transl Stroke Res 4:189-200. 2013
    ..These results suggest that VEGF has a neuroprotective effect, in part by enhancing endogenous angiogenesis. These data contribute to a better understanding of neonatal stroke. ..

Research Grants30

  1. The Role of Novel Angiogenic Signals in Post-Stroke Neurogenesis
    ANDREW JOHN BRUMM; Fiscal Year: 2013
    ..As there are currently no treatments to promote post-stroke functional recovery, such signaling systems may be valuable targets for neural repair in human stroke. ..
  2. INITIATION OF HUMAN LABOR: PREVENTION OF PREMATURITY
    Carole R Mendelson; Fiscal Year: 2013
    ..We propose that these interrelated projects, carried out by a highly interactive research team, will achieve the long-range goals of this Program and contribute to a reduction in the incidence of preterm birth. ..
  3. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  4. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  5. CHEMOKINE RECEPTOR FUNCTION IN THE NERVOUS SYSTEM
    Richard J Miller; Fiscal Year: 2013
    ....
  6. Regulation of Stromal Derived Factor-1 Mediated Angiogenesis in Ischemic Brain
    Umadevi V Wesley; Fiscal Year: 2013
    ..Results from these studies may provide strong foundation for better understanding of novel targets and mechanisms of brain injury repair and may also open up a new direction for stroke therapy. ..
  7. Indiana University Center for Pediatric Pharmacology
    Jamie L Renbarger; Fiscal Year: 2013
    ..The direct outcome of these studies will be new biomarkers and predictive signatures that will increase the precision of the existing dosing schemas used in the treatment of childhood cancer. ..