Survival of motor and proprioceptive neurons is essential to the organism and their loss or degeneration in man leads to serious neurological diseases such as spinal muscular atrophies (SMA), amyotrophic lateral sclerosis (ALS) or peripheral neuropathies. Several factors that keep motoneurons alive have recently been identified, and they form the basis of a novel therapeutic strategy to slow pathological motoneuron loss in man.
AIMS: by a combination of in-vivo and in-vitro approaches, we will characterize the actions of known and novel neurotrophic factors in the neuromuscular system (biological effects, signalling pathways, cellular targets). We will exploit the accessibility of the neuromuscular junction to provide new information on the role of such factors in synaptogenesis. The role of intrinsic factors in modulating neurotrophic effects will be evaluated in this system. The results should provide important input for future clinical trials in motoneuron diseases. SPECIFIC OBJECTIVES: 1) Role of muscle- and Schwann cell-derived factors in survival of motor and proprioceptive neurons 1.1: Identification of markers for functional sub-populations of motoneuron 1.2: Roles of GDNF (glial cell line-derived neurotrophic factor) and cytokines in survival of motor and proprioceptive neurons
1.3: Synergistic actions of neurotrophic factors on motor and proprioceptive neurons
1.4: Development of technology required for study of isolated mouse motoneurons 2) Role of neurotrophic factors in synapse formation and function 2.1: Analysis of neuromuscular junctions in transgenic and knockout mice 2.2: Effects of changed levels of neurotrophic factors on synaptogenesis at ectopic sites in soleus muscle
3) Intrinsic influences on motoneuron growth and survival
3.1: Growth and survival characteristics of motoneurons related to target distance
3.2: Intracellular mechanisms regulating motoneuron apoptosis TECHNOLOGICAL ASPECTS:
a multi-disciplinary approach will be taken, involving cellular and molecular biology, culture of purified neuronal populations, transgenic mouse technology and molecular genetics. New techniques will be developed for purification of motoneurons from mice.
Funding SchemeCSC - Cost-sharing contracts
171 77 Stockholm
KY16 9AJ St Andrews