NEURONAL PLASTICITY IN ALS SPINAL CORD NEURONS

描述：（申请人摘要）本提案的重点是

DESCRIPTION: (Applicant's Abstract) The focus of this proposal is to examined the consequential and causal events associated with motoneuron degeneration in amyotrophic lateral sclerosis (ALS). Current theories regarding the pathogenesis of motoneuron loss in ALS include, but are not limited to, central nervous system (CNS) excitotoxicity, autoimmune responses, mutations in the superoxide dismutase gene if familial ALS, na central or peripheral loss of trophic support. Interestingly, these events have also been shown to be involved in processes associated with programmed cell death, or apoptosis. The first Specific Aim of the present application is to study the expression of markers of programmed cell death in ALS autopsy material. This will be done by examining ALS and control spinal cord and motor cortex sections for cells exhibiting DNA fragmentation, a characteristic of apoptosis. In the second Specific Aim, we will use in situ hybridization and, in some cases, immunocytochemistry, to investigate the expression of certain cell death genes and their protein products in ALS tissue. The third Specific Aim will involve the screening of ALS cerebral spinal fluid (CSF) for the presence of immunoglobulins (e.g.Fas/Apo-1) known to be involved in programmed cell death. The outcome of these studies will determine the role of programmed cell death in ALS, and provide insight into potential therapeutic strategies to block this cell death process. One therapeutic approach currently being investigated is the treatment of ALS patients with neurotrophic factors. The rationale for using these molecules to treat ALS includes the understanding that neurotrophic factors promote neuronal survival and regrowth processes, and that they show some degree of selectivity for the populations of neurons in which they are effective. If trophic factor therapies are to be effective, it is essential to demonstrate that ALS motoneurons exhibit the capacity to respond to this treatment strategy. An initial step is the demonstration that ALS motoneurons express the receptors necessary for trophic factor signal transduction. The fourth Specific Aim will investigate the expression of the receptors for those trophic factors currently under investigation as therapeutic agents in the treatment of ALS. These receptors include the trks, which are the high-affinity receptors for the neurotrophins, and the alpha subunit of the CNTF receptor. We will use in situ hybridization to study the expression of specific mRNA encoding these receptors in ALS autopsy material. In addition, should adequate antibodies to the neurotrophic factor receptor proteins become available, we will incorporate the logical immunocytochemical experiments to compliment the study of mRNA expression. Overall, these studies are designed to advance our understanding of motoneuron degeneration in ALS, whether these motoneurons maintain the capacity to respond to certain trophic factor treatments, and demonstrate the potential role of programmed cell death in this devastating neurodegenerative disorder.