NEUROTROPHIN PROTECTION OF STRESSED CHOLINERGIC NEURONS

Project: Research project

Project Details

Description

DESCRIPTION (From the applicant's abstract): I have demonstrated that
neurotrophins (NTs) protect cultured embryonic rat basal forebrain cholinergic
neurons during hypoglycemic stress. The goal of the proposed study is to
identify important second messenger and early effector pathways involved in
this protection. Many of the experiments will utilize cholinergic neurons
purified by immunopanning. I have preliminary evidence that the following
contribute importantly to NT-mediated protection of cholinergic neurons during
hypoglycemic stress: (1) activation of phosphotidyl inositol (PI) 3-kinase, and
(2) activation of NF-kB (perhaps) via the p75 NT receptor (p75NTR).
Receptor-blocking antibodies, neurons from receptor-deficient mice, and mutant
forms of nerve growth factor (NGF) will be used to test the involvement of the
p75 NTR and TrkA NGF receptors. Assays of kinase activity and
immunohistochemical staining for activated forms of signalling molecules will
be used to clarify the stress-protective pathways activated by NTs under
hypoglycemic conditions. Inhibitors and activators of specific kinases and
introduction (by transfection) of mutant kinases will be tested to determine
whether they block, mimic or occlude NT-mediated protection.

To investigate early effector pathways by which NTs might produce their
stress-protection, imaging techniques will be used to measure NT effects on
cytosolic [Na+] and [Ca2+], mitochondrial [Ca2+] and mitochondrial membrane
potential. Alternative energy substrates, respiration measurements and
inhibitors of specific mitochondrial complexes will be tested to determine
whether NT-mediated protection requires up-regulation of plasma membrane
glucose transporters and/or alterations in mitochondrial energy and/or Ca2+
metabolism.

I have recently discovered that certain bone morphogenetic proteins (BMPs)
robustly enhance NT-mediated protection during hypoglycemic stress, and the
proposed experimental plan integrates studies to uncover basic mechanisms
underlying this synergistic effect.
StatusFinished
Effective start/end date12/31/893/31/05

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $333,450.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $337,500.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $337,500.00
  • National Institute of Neurological Disorders and Stroke: $337,500.00
  • National Institute of Neurological Disorders and Stroke

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