The long term goal of the proposed research is to examine the role of a variety of purified neurotrophic agents in promoting the survival and differentiation of mammalian neurons in vivo, including motoneurons (MNs), dorsal root ganglia (DRG), sympathetic ganglia, and spinal interneurons during normal development and following injury. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), ciliary neurotrophic factor (CNTF), and the muscle-derived protein, choline acetyltransferase development factor (CDF), will be used to treat mouse embryos in utero during periods of naturally occurring neuronal death. At the end of the cell death period, treated and control embryos will be evaluated regarding the development of a number of different properties of peripheral and central neurons. These include measures of neuron survival and differentiation and measures of target development and innervation. In addition, we will determine whether the injury-induced death of motor and sensory neurons that occurs following axotomy of peripheral nerves in fetal and neonatal mice can be prevented by treatment with these trophic agents. We will also examine whether postnatal administration of these proteins alters the development of normal neuron properties such as soma size, dendritic arbors, and biochemical differentiation. Previous studies have shown that some of the trophic agents to be employed here promote sensory, sympathetic, and motor neuron survival in vivo in the chick embryo. The planned studies are novel in that they represent the first attempt to demonstrate an in vivo effect of neurotrophic agents, including muscle- derived agents, on mammalian MN development and survival. These studies are an important step in determining whether trophic agents are involved in the death of MNs in motor neuron disease and may be especially significant for understanding the pathological mechanisms in Infantile Progressive Spinal Muscular Atrophy (Werdnig-Hoffman Disease) and Amyotrophic Lateral Sclerosis (ALS).

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029435-02
Application #
3330909
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1992-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Houenou, L J; Blondet, B; Li, L et al. (1996) The paralyse mouse mutant: a new animal model of anterior horn motor neuron degeneration. J Neuropathol Exp Neurol 55:698-703
Houenou, L J; Li, L; Lei, M et al. (1996) Exogenous heat shock cognate protein Hsc 70 prevents axotomy-induced death of spinal sensory neurons. Cell Stress Chaperones 1:161-6
Li, L; Schatteman, G C; Oppenheim, R W et al. (1996) Altered development of spinal cord in the mouse mutant (Patch) lacking the PDGF receptor alpha-subunit gene. Brain Res Dev Brain Res 96:204-9
Houenou, L J; Oppenheim, R W; Li, L et al. (1996) Regulation of spinal motoneuron survival by GDNF during development and following injury. Cell Tissue Res 286:219-23
Li, L; Wu, W; Lin, L F et al. (1995) Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor. Proc Natl Acad Sci U S A 92:9771-5
Houenou, L J; Turner, P L; Li, L et al. (1995) A serine protease inhibitor, protease nexin I, rescues motoneurons from naturally occurring and axotomy-induced cell death. Proc Natl Acad Sci U S A 92:895-9
Lo, A C; Houenou, L J; Oppenheim, R W (1995) Apoptosis in the nervous system: morphological features, methods, pathology, and prevention. Arch Histol Cytol 58:139-49
Lo, A C; Li, L; Oppenheim, R W et al. (1995) Ciliary neurotrophic factor promotes the survival of spinal sensory neurons following axotomy but not during the period of programmed cell death. Exp Neurol 134:49-55
Li, L; Oppenheim, R W; Lei, M et al. (1994) Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse. J Neurobiol 25:759-66
Houenou, L J; Li, L; Lo, A C et al. (1994) Naturally occurring and axotomy-induced motoneuron death and its prevention by neurotrophic agents: a comparison between chick and mouse. Prog Brain Res 102:217-26

Showing the most recent 10 out of 11 publications