GDNF: EFFECTS ON NORMAL AND DEGENERATING MOTOR NEURONS

描述（由申请人提供）：运动神经元疾病（MND）是一种 一组以进行性虚弱为特征的退行性疾病， 骨骼肌萎缩导致受影响个体的最终死亡。 上和/或下运动神经元（MN）的选择性变性是运动神经元的选择性变性。 这些疾病的标志，其中最常见的是在成人肌萎缩 侧索硬化症（ALS）。临床上几乎没有成功， 治疗ALS和其他MND。神经营养因子（NF）已被认为是 作为治疗这些疾病的潜在药物;然而， 在ALS试验中没有表现出任何有益的效果。公 认识到一个主要问题是这些因素的外周传递。我们 主要的兴趣集中在GDNF家族配体上，因为GDNT是最重要的配体。 迄今已知的有效MN存活因子。了解这些机制， GDNF在发育过程中和神经元发育后促进MN存活 损伤及其对靶组织神经支配的影响， 深入了解MN生物学，并帮助确定GDNF的治疗价值， MN疾病的治疗。转基因方法将用于研究 GDNF在正常和病理条件下对MN的重要性，从而允许 我们比较了GDNF在MN靶组织中的过表达与 中枢神经系统（CNS）。已经表明， 某些NF的效果确实取决于递送途径。本申请中 我们将检验GDNF的传递途径可能 显著影响其对MNs存活作用，并使GDNF过表达 将使MN免于程序性细胞死亡（PCD）， 在轴突切断后产生MN的长期存活。此外，我们将测试 GDNF在MN疾病小鼠模型中的潜在保护作用， 确定其有效性是否依赖于GDNF表达的位点（CNS 相对于外周靶组织）。在具体目标1中，我们将在体内研究 GDNF（通过不同途径递送）对MN PCD的作用。在目标2中，我们将 确定GDNF是否促进MN的长期存活， 轴突切断术和永久性防止神经肌肉突触消除 交界处。在目标3中，我们将测试GDNF可能的保护作用， 家族性ALS的小鼠模型，沿着其途径的重要性， 局在目标4中，我们将测试GDNF在一个 自然发生的小鼠模型MN变性，进行性运动 神经元病（PMN）小鼠。这些研究应该为我们提供新的见解， GDNF在正常和病理条件下对MN的体内作用，并定义 GDNF递送至MN的各种模式之间的差异。他们将 也进一步明确了GDNF在治疗MND中的潜力，并帮助设计 合适的战略来实现。

DESCRIPTION (provided by the applicant): Motor neuron diseases (MND) are a group of degenerative disorders characterized by progressive weakness and atrophy of skeletal muscle leading to eventual death of affected individuals. The selective degeneration of upper and/or lower motor neurons (MN) is the hallmark of these diseases, the most common of which in adults is Amyotrophic Lateral Sclerosis (ALS). Little clinical success has been reached for the treatment of ALS and other MNDs. Neurotrophic factors (NF) have been considered as potential agents for treatment of these diseases; however, several NFs failed to demonstrate any beneficial effects in ALS trials. It is well recognized that a major issue is the peripheral delivery of these factors. Our primary interest has focused on the GDNF family ligands, since GDNT is the most potent MN survival factor known to date. Understanding the mechanisms, by which GDNF acts to promote MN survival during development and following neuronal injury, as well as its effect on the innervation of target tissue, may give insight into MN biology and help define a therapeutic value for GDNF in the treatment of MN diseases. A transgenic approach will be used to study the importance of GDNF on MNs in normal and pathological conditions, thus allowing us to compare the effects of GDNF over expression in MN target tissue with that in the Central Nervous System (CNS). It has been shown that the beneficial effects of some NFs indeed depend on the route of delivery. In this application we will test the hypothesis that the route of delivery of GDNF may significantly impact its survival effects on MNs, and that GDNF over expression in transgenic mice will rescue MNs from programmed cell death (PCD), and produce long-term survival of MNs after axotomy. In addition, we will test GDNF's potential protective effects in mouse models of MN disease, and determine if its effectiveness is dependent on the site of GDNF expression (CNS vs. peripheral target tissue). In specific aim 1, we will study in vivo the role of GDNF (delivered via different routes) on MN PCD. In aim 2, we will determine whether GDNF promotes both long-term survival of MN following axotomy, and permanent prevention of synapse elimination at the neuromuscular junction. In aim 3, we will test the possible protective effects of GDNF in a murine model of Familial ALS, along with the importance of its route of administration. And in aim 4, we will test the protective effect of GDNF in a naturally occurring mouse model of MN degeneration, progressive motor neuronopathy (pmn) mice. These studies should provide new insight into the in vivo role of GDNF on MNs in both normal and pathological conditions, and define the differences between the various modes of GDNF delivery to MNs. They will also further define the potential of GDNIF in treating MNDs, and help design suitable strategies for its delivery.