CILIARY NEUROTROPHIC FACTOR RECEPTORS AND NEUROPROTECTIO

描述：(逐字摘自申请者的摘要)大量数据 这表明，自然生长因子机制限制了次要的， 创伤性中枢神经系统损伤的神经退行性改变。特别增强了 这些内源性的神经保护机制应该是一种有效的方法 在治疗创伤的同时产生的副作用比更广泛的更少 有针对性的治疗。识别和描述这些机制 细胞和分子水平是开发技术的明显先决条件。 专门操纵它们。 大量间接研究表明，睫状神经营养因子 运动神经元CNTF受体在损伤后可能被自然激活 这种激活可能会保护神经元免受神经退行性变化的影响 受伤的原因。然而，所有公开发表的证据表明， CNTF受体是间接的，主要是因为该领域缺乏方法来 体内定位特异性拮抗CNTF受体活性。我们有 最近开发了一种新的方法，可以在 体内亚细胞水平的分辨率。我们已经使用这种测试来证明 结论：1)脑和脊髓运动神经元的CNTF受体是选择性的 对CNTF敏感和2)AADH-CNTF，CNTF的突变形式，特异性 在体内拮抗运动神经元CNTF受体。我们还开发了一个In 首例面神经运动核损伤活体模型的建立 损伤诱导的CNTF受体的刺激。此外，在此模型中， 具有激活的CNTF受体的运动神经元几乎没有细胞死亡或 ChAT活性的丧失，从而表明CNTF受体的活性可能 成为自然神经保护过程的一部分。我们建议将其描述为 受体刺激(特定目标1)，并定义其对 成活(特定目标2)和表型维持(特定目标3) 在体面运动神经元CNTF受体拮抗面运动神经元 用AADH-CNTF。此外，内源性CNTF的参与将是 通过使用功能阻断抗体进行研究(特定目标4)。最后， 结果的一般性将通过类似的角色研究来检验 CNTF受体和CNTF在三叉神经运动神经元损伤反应中的作用 (具体目标5)。

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).