Cellular Mechanisms of Fetal White Matter Injury

Project: Research project

Description

DESCRIPTION (provided by applicant): Periventricular leukomalacia (PVL) is the major form of brain injury in the premature infant. During critical illness, PVL is related to hypoxia-ischemia, and results in cerebral palsy, the leading cause of chronic neurological disability in survivors of premature birth. Since the death of oligodendrocyte (OL) progenitors could explain the myelination disturbances that are the major pathological feature of PVL, we studied a true fetal model to determine the acute response of the white matter to ischemia. Graded selective periventricular white matter injury was produced via a well-established in utero model in the 0.65 gestation sheep that mimics acute global cerebral ischemia. Injury is accompanied by death of OL progenitors and suggests an explanation for the developmental specificity of PVL. We will test the hypothesis that the predilection of cerebral white matter to injury is primarily related to maturation-dependent vulnerability of oligodendrocyte (OL) progenitors whose death is related to free radical toxicity from oxidative stress, and secondarily that such stress occurs at distinct sites of particularly marked blood flow disturbances during the course of global cerebral hypoperfusion-reperfusion. Our approach is a significant departure from previous studies in that we will focus on cellular mechanisms of white matter injury. We will precisely determine the relative susceptibility of successive stages in the OL lineage to death from in utero ischemia with OL lineage-specific markers. A multidisciplinary approach will integrate recent advances in immunohistochemistry, in situ analysis of regional cerebral blood flow with fluorescent microspheres, and oxidant biochemistry to investigate mechanisms of free radical-mediated white matter injury. Our long term objectives are to define the pathophysiologic relationships among ischemia, acute white matter damage and mechanisms of oligodendroglial vulnerability in periventricular white matter. The specific aims to be studied are: (1) Determine whether the susceptibility of the OL lineage to global ischemia in utero is maturation-dependent. (2) Determine the extent and spatial distribution of the acute global ischemia and its relationship to regions of cerebral white matter injury. (3) Determine molecular mechanisms of oxidative stress related to the pathogenesis of cerebral white matter injury from global ischemia. Upon completion of this project, we hope to gain insight into strategies to prevent PVL by understanding intrinsic features of the OL progenitor which influence susceptibility to free radical-mediated injury from ischemia.
StatusActive
Effective start/end date2/1/033/31/20

Funding

  • National Institutes of Health: $543,121.00
  • National Institutes of Health: $237,206.00
  • National Institutes of Health: $377,300.00
  • National Institutes of Health: $336,875.00
  • National Institutes of Health: $237,206.00
  • National Institutes of Health: $325,063.00
  • National Institutes of Health: $78,803.00
  • National Institutes of Health: $333,507.00
  • National Institutes of Health: $249,318.00
  • National Institutes of Health: $280,158.00
  • National Institutes of Health: $597,714.00
  • National Institutes of Health: $49,049.00
  • National Institutes of Health: $336,875.00
  • National Institutes of Health: $364,095.00
  • National Institutes of Health: $377,300.00
  • National Institutes of Health: $84,788.00

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Wounds and Injuries
Ischemia
Oligodendroglia
Periventricular Leukomalacia
Premature Birth
Cerebrovascular Circulation
White Matter
Cerebral Palsy
Brain Ischemia
Sheep
Brain Injuries
Gliosis
Free Radicals
Neurons
Atrophy
Axons
Electroencephalography
Animal Models
Mothers
Oxidative Stress

ASJC

  • Medicine(all)
  • Neuroscience(all)