CILIARY NEUROTROPHIC FACTOR RECEPTORS AND NEUROPROTECTIO

点击翻译按钮获取中文摘要

DESCRIPTION: (Verbatim from the Applicant's Abstract) A large body of data suggests that natural growth factor mechanisms limit the secondary, neurodegenerative effects of traumatic CNS injuries. Specifically enhancing these endogenous, neuroprotective mechanisms should be a powerful method of treating the injuries while producing fewer side effects than more broadly targeted therapies. Identifying and characterizing these mechanisms at a cellular and molecular level are obvious prerequisites to developing techniques to specifically manipulate them. A wide variety of indirect studies suggest that the ciliary neurotrophic factor (CNTF) receptors of motor neurons may be naturally activated following injury and that this activation may protect the neurons from neurodegenerative effects of injury. However, all the published evidence suggesting such a role for the CNTF receptor is circumstantial, primarily because the field lacks methods to localize the specifically antagonize CNTF receptor activity in vivo. We have recently developed a novel assay which can localize CTF receptor activity at a subcellular level of resolution in vivo. We have used this assay to demonstrate that: 1) cranial and spinal motor neuron CNTF receptors are selectively sensitive to CNTF and 2) AADH-CNTF, a mutant form of CNTF, specifically antagonizes motor neuron CNTF receptors in vivo. We have also developed an in vivo model of facial motor nucleus injury which has revealed the first example of injury-induced stimulation of CNTF receptors. Moreover, in this model, the motor neurons with activated CNTF receptors display little to no cell death or loss of ChAT activity, thereby suggesting that the CNTF receptor activity may be part of a natural neuroprotective process. We propose to characterize this receptor stimulation (Specific Aim 1) and define its contributions to the survival (Specific Aim 2) and phenotype maintenance (Specific Aim 3) of the facial motor neurons by antagonizing facial motor neuron CNTF receptors in vivo with AADH-CNTF. In addition , the participation of endogenous CNTF will be studied by employing function-blocking antibodies (Specific Aim 4). Finally, the generality of the results will be examined by similarly studying the role of CNTF receptors and CNTF in trigeminal motor neuron responses to injury (Specific Aim 5).