CELLULAR MECHANISMS FOR NERVE REPAIR

Project: Research project

Project Details

Description

DESCRIPTION (Verbatim from Applicant's Abstract): A major problem in
neurobiology concerns the mechanisms by which damaged neurons may re-grow axons
and form selective connections to restore function. We propose to test the role
of migrating microglia in successful axonal regeneration that follows injury to
the leech nervous system. Migration of microglia occurs promptly, accounts for
the increase in cell numbers at the lesion, and appears influenced by nitric
oxide synthase activity, which is rapidly up regulated at the lesion.
Microglial migration is also affected by applied electric fields of a size
consistent with injury currents we measure at the lesion. Evidently microglia
deposit laminin, a component of the extracellular matrix that promotes axon
growth. The leech is particularly advantageous for these studies because (1)
its ganglia contain identifiable neurons capable of regenerating specific
connections following axotomy, (2) individual microglia can be tracked and
their movements charted minute by minute, and (3) adult and embryonic nervous
systems can be manipulated and examined both in vivo and in vitro. Experiments
that interfere with and block accumulation of microglia at injury sites will
test the role of microglia in sprouting and regeneration. Immunocytochemistry
has shown abundant laminin transiently in the embryonic leech nervous system
along axon pathways. Following injury to the adult nervous system, laminin
reappears (first in patches at the lesion, later in streaks) in advance of
axons. Whether the microglia that migrate toward the site of the lesion produce
the laminin, as in vitro, will be determined using antibodies and in situ
hybridization with our riboprobes for laminin. We will determine whether the
streaks of laminin, which may guide regenerating axons, mark the paths of
migrating microglial cells; fluorescently labeled microglia will be tracked in
living preparations using low-light video microscopy. Alterations of nitric
oxide levels and its synthesis and of electric fields such as those generated
by the lesion will determine the actions of nitric oxide and fields in
regulating microglial migration. These studies will clarify the roles of
microglia and of laminin in axonal regeneration following injury, and may
suggest strategies for achieving equally successful axonal repair in the
mammalian nervous system.
StatusFinished
Effective start/end date7/18/996/30/05

Funding

  • National Institute of Neurological Disorders and Stroke: $246,407.00
  • National Institute of Neurological Disorders and Stroke: $253,482.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $260,768.00
  • National Institute of Neurological Disorders and Stroke: $30,393.00

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