GDNF: EFFECTS ON NORMAL AND DEGENERATING MOTOR NEURONS

描述(申请人提供)：运动神经元病(MND)是 一组退行性疾病，特征是进行性虚弱和 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 这些疾病的标志是肌萎缩侧索硬化症，其中最常见的是成人 侧索硬化(ALS)。在临床上几乎没有取得成功。 治疗肌萎缩侧索硬化症和其他MND。神经营养因子(NF)已被考虑 作为治疗这些疾病的潜在药物；然而，几种非传染性疾病 在肌萎缩侧索硬化症试验中未能证明任何有益的效果。这很好 认识到一个主要问题是这些因素的外围交付。我们的 人们的主要兴趣集中在GDNF家族的配体上，因为GDNT是 到目前为止已知的有效的MN生存因素。了解机制，通过这些机制 GDNF促进MN在发育过程中和后续神经元的存活 损伤及其对靶组织神经支配的影响可能会导致 深入了解MN生物学并帮助确定GDNF在 MN疾病的治疗。将使用转基因方法来研究 在正常和病理条件下，GDNF在MNS中的重要性，从而允许 美国将比较GDNF在MN靶组织中过表达的作用 在中枢神经系统(CNS)。已经证明，有益于 一些非正规医疗服务的效果确实取决于投放的途径。在此应用程序中 我们将检验这一假设，即GDNF的传递途径可能 显著影响其对MNS的生存效应，且GDNF过表达 将MNS从程序性细胞死亡(PCD)中拯救出来，以及 能使MNS在轴突切断后长期存活。此外，我们还将测试 GDNF对MN病小鼠模型的潜在保护作用 确定其有效性是否依赖于GDNF的表达部位(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(通过不同途径传递)在MN PCD中的作用。在目标2中，我们将 确定GDNF是否促进以下MN的长期生存 轴突切断术和永久防止神经肌肉突触消除 交叉口。在目标3中，我们将测试GDNF对小鼠的可能的保护作用 家族性肌萎缩侧索硬化症的小鼠模型及其发病途径的重要性 行政管理。在目标4中，我们将测试GDNF对小鼠的保护作用 自然发生的MN变性、进行性运动的小鼠模型 神经病(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MNS的活体作用，并定义 向MNS提供GDNF的不同方式之间的差异。他们会 还进一步确定了GDNIF在治疗MND方面的潜力，并帮助设计 适用于其交付的策略。

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.